Assoc. Prof. Ivan Lambeve-mail: itlambev@mail.bg

Antifungal drugsAntifungal drugs

Human fungal infections have increased dramaticallyin recent years, owing mainly to advances in surgery,cancer treatment, and critical care accompanied by increases in the use of broad-spectrum antimicrobialsand the HIV epidemic.

Fungal infections are usually more difficult to treatthan bacterial infections, because fungal organisms growslowly and because fungal infections often occur in tissues that are poorly penetrated by antimicrobial agents(e.g., devitalized or avascular tissues). Therapy of fungalinfections usually requires prolonged treatment.

Superficial fungal infectionsSuperficial fungal infections involve cutaneous involve cutaneous surfaces (skin, nails, and hair), and mucous membranesurfaces (skin, nails, and hair), and mucous membranesurfaces (oropharynx and vagina). surfaces (oropharynx and vagina).

DeepDeepseated or disseminated fungal infectionsseated or disseminated fungal infections caused causedby dimorphic fungi, the yeasts Cryptococcus neoformans,by dimorphic fungi, the yeasts Cryptococcus neoformans,and various Candida spp. respond to a limited number and various Candida spp. respond to a limited number of systemic agents: amphotericin B (a polyene), of systemic agents: amphotericin B (a polyene), flucytosine (a pyrimidine antimetabolite), the newerflucytosine (a pyrimidine antimetabolite), the newerazoles (ketoconazole, fluconazole, itraconazole, andazoles (ketoconazole, fluconazole, itraconazole, andvoriconazole), and voriconazole), and caspofungin (an echinocandin)caspofungin (an echinocandin)..

I. AntifI. Antifungalungalss damagingdamaging permeability permeability of the cell membraneof the cell membrane

•Imidazoles:Imidazoles: Bifonazole, Clotrimazole, Econazole, Bifonazole, Clotrimazole, Econazole, Ketoconazole, MiconazoleKetoconazole, Miconazole•Triazoles:Triazoles: Fluconazole, Itraconazole, Voriconazole Fluconazole, Itraconazole, Voriconazole•AAllylaminellylaminess:: Terbinafine, Naftifine Terbinafine, Naftifine•MorpholinMorpholineses:: Amorolfine Amorolfine•Thiocarbamates:Thiocarbamates: Tolciclate, Tolnaftate Tolciclate, Tolnaftate•Substituted pyridonesSubstituted pyridones: Ciclopirox: Ciclopirox•PPolyene antibiotics:olyene antibiotics: Amphotericin B, Nystatin Amphotericin B, Nystatin

II. II. Antifungals inhibiting chitin synthesis in the cell wallAntifungals inhibiting chitin synthesis in the cell wall•Caspofungin, GriseofulvinCaspofungin, Griseofulvin

III. III. Antifungals inhibiting synthesis of nucleic acidsAntifungals inhibiting synthesis of nucleic acids•FlucytosineFlucytosine

1. Polyene antibiotics

Amphotericin B and Nystatin bind to the fungalcell membrane component ergosterol, leading to increased fungal cell membrane permeability andthe loss of intracellular constituents. Amphotericin hasa lesser affinity for the mammalian cell membranecomponent cholesterol, but this interaction does account for most adverse toxic effects.Amphotericin B has activity against Candida spp., Cryptococcus neoformans, Blastomyces dermatitidis,Histoplasma capsulatum, Sporothrix schenckii,Coccidioides immitis, Paracoccidioides braziliensis,Aspergillus spp., Penicillium marneffei, etc.

Amphotericin uses i.v.i.v. for treatment of Candida esopha-gitis, rapidly progressive mucormycosis or invasive aspergillosis. Intrathecal infusion of amphotericin B isuseful in patients with meningitis caused by Coccidioides.Intravenous administration of amphotericin B is the treatment of choice for mucormycosis and is used for theinitial treatment of cryptococcal meningitis, severe orrapidly progressing histoplasmosis, blastomycosis, and coccidioidomycosis. Intraocular injection hasbeen used successfullyfor fungal endophthalmitis.

The major acute reaction to i.v. amphotericin B is fever and chills. Tachypnea and respiratory stridoror modest hypotension also may occur. Patients withpreexisting cardiac or pulmonary disease may tolerate the metabolic demands of the reaction poorly and develop hypoxia or hypotension. Although the reaction ends spontaneously in 30 to 45 minutes, pethidine may shorten it. Pretreatment with oral paracetamol or use of i.v.hydrocortisone hemisuccinate, at the start of the infusion decreases reactions. Azotemia occurs in80% of patients who receive amphotericinin deep mycoses.

Several lipid formulations of amphotericin B – colloidal dispersion and liposomal amphotericin B, have beendeveloped in an attempt to reduce the toxicity profileof this drug and to increase its efficacy. Formulatingamphotericin with lipids alters drug distribution, withlower levels of drug in the kidneys, reducing the incidence of nephrotoxicity. While less toxic, thelipid formulations are significantly more expensivethan conventional amphotericin Bamphotericin B.

Polyene bindsPolyene binds

Nystatin is a polyenea polyene antifungal drug with a ring structure and a mechanism of action similar to that of amphotericin B. Too toxic for systemic use, nystatin is limited to the topical treatment of superficial infections caused by C. albicans. Infections commonlytreated by this drug include oral candidiasis(thrush), mild esophageal candidiasis, and vaginitis.

2. Antifungal Azoles are synthetic drugswith broad-spectrum fungistatic activity. Azoles can bedivided into two groups: the older imidazole agents (clotrimazole, ketoconazole, miconazole) in whichthe five-member azole nucleus contains two nitrogensand the newer triazole compounds (fluconazole, itraconazole, and voriconazole), in which the azole nucleus contains three nitrogens.

All azoles exert antifungal activity by inhibitingcytochrome P450 enzymes responsible for the demethylation of lanosterol to ergosterol. Reduced fungal membrane ergosterol concen-trations result in damaged, leaky cell membranes. The toxicity of these drugs depends ontheir relative affinities for mammalian and fungalcytochrome P450 enzymes. The triazoles tend to have fewer side effects, better absorption, better drug distribution in body tissues, and fewer drug interactions.

Fluconazole does not require an acidic environment, as does ketoconazole, for GI absorption. About 80 to 90% of an orally administereddose is absorbed, yielding high serum drug levels. Thet1/2 of the drug is 27 to 37 h, permitting once-dailydosing in patients with normal renal function. Only 11%of the circulating drug is bound to plasma proteins.The drug penetrates widely into most body tissues. Cerebrospinal fluid levels are 60 to 80% of serum levels,permitting effective treatment for fungal meningitis. About 80% of the drug is excreted unchanged in the urine. Dosage reductions are required in the presenceof renal insufficiency.

Fluconazole is very effective in the treatment of infec-tions with most Candida spp. Thrush in the end-stageAIDS patient, often refractory to nystatin, clotrimazole,and ketoconazole, can usually be suppressed with oralfluconazole. AIDS patients with esophageal candidiasisalso usually respond to fluconazole. A single 150 mgdose has been shown to be an effective treatment forvaginal candidiasis. A 3-day course of oral fluconazole isan effective treatment for Candida urinary tract infection.Stable non-neutropenic patients with candidemiacan be adequately treated with fluconazole.

Fluconazole may be an alternative to amphotericin Bin the initial treatment of mild cryptococcalmeningitis and coccidioidal meningitis.

A significant decrease in mortality from deep-seatedmycoses was noted among bone marrow transplantrecipients treated prophylactically with fluconazole. Fluconazole taken prophylactically by end-stage AIDSpatients can reduce the incidence of cryptococcal meningitis, esophageal candidiasis, and superficial fungal infections.

Fluconazole is well tolerated. Asymptomatic liver enzymeelevation has been described, and several cases of drug associated hepatic necrosis have been reported.

Alopecia has been reported as a common adverse eventin patients receiving prolonged high-dose therapy. Coadministration of enzyme inhibitor fluconazole withphenytoin results in increased serum phenytoin levels.

Itraconazole is lipophilic and water insoluble and requires a low gastric pH for absorption.Oral bioavailability is variable (20 to 60%). It ishighly protein bound (99%) and is metabolizedin the liver and excreted into the bile.Itraconazole is most useful in the long-term suppressivetreatment of disseminated histoplasmosis in AIDS andin the oral treatment of nonmeningeal blastomycosis.

It is the drug of choice for all forms of sporotrichosisexcept meningitis. Itraconazole has replaced ketoconazole as the drug of choice in the treatmentof paracoccidioidomycosis and chromomycosis.

Sporo-trichosis

Sporothrix schenkii

Ketoconazole (Nizoral®) can be absorbed orally, but it requires an acidic gastric environment.It remains useful in the treatment of cutaneous andmucous membrane dermatophyte and yeast infections,but it has been replaced by the newer triazoles in thetreatment of most serious Candida infections and disseminated mycoses. Ketoconazole is usually effective in the treatment of thrush, but fluconazoleis superior to ketoconazole for refractory thrush.Widespread dermatophyte infections on skin surfacescan be treated easilywith oral ketoconazole. Thrush

Nausea, vomiting, and anorexia occur commonly withketoconazole when high doses are prescribed. Epigastric distress can be reduced by taking ketoconazolewith food. Pruritis and/or allergic dermatitis occurs in10% of patients. Liver enzyme elevations during therapyare usually reversible. Severe ketoconazole-associated hepatitis is rare. At high doses,ketoconazole causes a clinically significantreduction in testosterone synthesis and blocksthe adrenal response to corticotrophin. Gynecomastia,impotence, reduced sperm counts, and diminished libidocan occur in men, and prolonged drug use can resultin irregular menses in women. These hormonal effectshave led to the use of ketoconazole as a potentialadjunctive treatment for prostatic carcinoma.

Clotrimazole is a broad-spectrum fungistatic imidazole drug used in the topical treatment of oral, skin, and vaginal infections with C. albicans. It isalso employed in the treatment of infections with cutaneous dermatophytes. Topical use results in therapeutic drug concentrations in the epidermisand mucous membranes; less than 10% of thedrug is systemically absorbed.

3. Fluorinated pyrimidinesFlucytosine (5-flucytosine, 5-FC)is an analogue of cytosine that was originallysynthesized for possible use as an antineoplasticagent. 5-FC is converted to 5-fluorouracil inside the cellby the fungal enzyme cytosine deaminase. The activemetabolite 5-fluorouracil interferes with fungal DNAsynthesis by inhibiting thymidylate synthetase.Incorporation of these metabolites into fungal RNA inhibits protein synthesis.Flucytosine has a significant antifungal activity againstCandida spp. and the fungal organisms responsiblefor chromomycosis.

4. Allylamines – reversible noncompetitiveinhibitors of the fungal enzyme squalenemonooxygenase, which converts squalene to lanosterol. With a decrease in lanosterol production, ergosterolproduction is also diminished, affecting fungal cellmembrane synthesis and function. These agents exhibit fungicidal activity against dermatophytesand fungistatic activity against yeasts.Naftifine is available for topical use only in the treat-ment of cutaneous dermatophyte and Candida infections.Terbinafine (Lamisil®) is available fortopical and systemic use (oral tablet) inthe treatment of dermatophyte skin and nail infections.

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5. EchinocandinsCaspofungin is a semisynthetic lipopeptide. Itinhibits the synthesis of beta-D-glucan, a cell wallcomponent of filamentous fungi. Caspofungin isapproved for the treatment of invasive aspergillosisin patients not responding to amphotericin B, and itraconazole.

Adverse effects are mediated through histamine release: facial flushing, rash, fever, and pruritus. Dose reductions are required in the presence ofmoderate hepatic insufficiency.

6. PyridonesCiclopirox olamine is a pyridone derivativefor the treatment of cutaneous dermatophyteinfections, cutaneous C. albicans infections,and tinea versicolor caused by Malassezia furfur. It interferes with fungal growth by inhibiting macromolecule synthesis.

7. ThiocarbamatesTolnaftate is an antifungal agent effective in the topical treatment of dermatophyte infections and tinea.

8. Nonpolyene antibioticsGriseofulvin is an oral fungistatic agent usedin the long-term treatment of dermatophyte infectionscaused by Epidermophyton, Microsporum, and Trichophyton spp. Produced by Penicilliumgriseofulvin, it inhibits fungal growth by binding to themicrotubules responsible for mitotic spindle formation. The drug binds to keratin precursor cellsand newly synthesized keratin in the stratum corneumof the skin, hair, and nails, stopping the progression ofdermatophyte infection. In the treatment of ringworm of the beard, scalp, and other skin surfaces, 4 to 6 weeks of therapy is often required.