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1 e-mail: email@example.com Antifungal drugsAssoc. Prof. Ivan Lambev
2 Human fungal infections have increased dramatically in recent years, owing mainly to advances in surgery,cancer treatment, and critical care accompanied byincreases 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 intissues that are poorly penetrated by antimicrobial agents(e.g., devitalized or avascular tissues). Therapy of fungalinfections usually requires prolonged treatment.
3 Deepseated or disseminated fungal infections caused Superﬁcial fungal infections involve cutaneoussurfaces (skin, nails, and hair), and mucous membranesurfaces (oropharynx and vagina).Deepseated or disseminated fungal infections causedby dimorphic fungi, the yeasts Cryptococcus neoformans,and various Candida spp. respond to a limited numberof systemic agents: amphotericin B (a polyene),ﬂucytosine (a pyrimidine antimetabolite), the newerazoles (ketoconazole, ﬂuconazole, itraconazole, andvoriconazole), and caspofungin (an echinocandin).
4 I. Antifungals damaging permeability of the cell membraneImidazoles: Bifonazole, Clotrimazole, Econazole,Ketoconazole, MiconazoleTriazoles: Fluconazole, Itraconazole, VoriconazoleAllylamines: Terbinafine, NaftifineMorpholines: AmorolfineThiocarbamates: Tolciclate, TolnaftateSubstituted pyridones: CiclopiroxPolyene antibiotics: Amphotericin B, NystatinII. Antifungals inhibiting chitin synthesis in the cell wallCaspofungin, GriseofulvinIII. Antifungals inhibiting synthesis of nucleic acidsFlucytosine
5 1. Polyene antibiotics Amphotericin B and Nystatin bind to the fungal cell membrane component ergosterol, leading toincreased fungal cell membrane permeability andthe loss of intracellular constituents. Amphotericin hasa lesser afﬁnity for the mammalian cell membranecomponent cholesterol, but this interaction doesaccount 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.
6 Amphotericin uses i.v. for treatment of Candida esopha- gitis, rapidly progressive mucormycosis or invasiveaspergillosis. Intrathecal infusion of amphotericin B isuseful in patients with meningitis caused by Coccidioides.Intravenous administration of amphotericin B is thetreatment 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.
7 80% of patients who receive amphotericin in deep mycoses. The major acute reaction to i.v. amphotericin B isfever and chills. Tachypnea and respiratory stridoror modest hypotension also may occur. Patients withpreexisting cardiac or pulmonary disease maytolerate the metabolic demands of the reactionpoorly and develop hypoxia or hypotension.Although the reaction ends spontaneously in 30 to45 minutes, pethidine may shorten it.Pretreatment with oral paracetamol or use of i.v.hydrocortisone hemisuccinate, at the start of theinfusion decreases reactions. Azotemia occurs in80% of patients who receive amphotericinin deep mycoses.
8 Polyene binds 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 theincidence of nephrotoxicity. While less toxic, thelipid formulations are signiﬁcantly more expensivethan conventional amphotericin B.Polyene binds
9 Nystatin is a polyene antifungal drug with a ring structure and a mechanism of actionsimilar to that of amphotericin B. Too toxicfor systemic use, nystatin is limited to thetopical treatment of superﬁcial infectionscaused by C. albicans. Infections commonlytreated by this drug include oral candidiasis(thrush), mild esophageal candidiasis,and vaginitis.
10 2. Antifungal Azoles are synthetic drugs with 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.
11 All azoles exert antifungal activity by inhibiting cytochrome P450 enzymes responsible for thedemethylation 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 inbody tissues, and fewer drug interactions.
13 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 theurine. Dosage reductions are required in the presenceof renal insufﬁciency.
14 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.
15 Fluconazole may be an alternative to amphotericin B in 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 cryptococcalmeningitis, esophageal candidiasis, andsuperﬁcial fungal infections.
16 Fluconazole is well tolerated. Asymptomatic liver enzyme elevation has been described, and several cases ofdrug 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.
17 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 replacedketoconazole as the drug of choice in the treatmentof paracoccidioidomycosis and chromomycosis.
19 Thrush 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 anddisseminated mycoses. Ketoconazole is usuallyeffective in the treatment of thrush, but ﬂuconazoleis superior to ketoconazole for refractory thrush.Widespread dermatophyteinfections on skin surfacescan be treated easilywith oralketoconazole.Thrush
20 Nausea, vomiting, and anorexia occur commonly with ketoconazole 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.
21 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 withcutaneous dermatophytes. Topical use results intherapeutic drug concentrations in the epidermisand mucous membranes; less than 10% of thedrug is systemically absorbed.
22 3. Fluorinated pyrimidines Flucytosine (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 RNAinhibits protein synthesis.Flucytosine has a significant antifungal activity againstCandida spp. and the fungal organisms responsiblefor chromomycosis.
23 4. Allylamines – reversible noncompetitive inhibitors 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 agentsexhibit 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 andnail infections.
24 ClearChoice™ uses two different and proven laser technologies (Q-Switched Nd: YAG) and (Pulsed Nd: YAG) to treat onychomycosis
25 5. Echinocandins Caspofungin is a semisynthetic lipopeptide. It inhibits the synthesis of beta-D-glucan, a cell wallcomponent of ﬁlamentous fungi. Caspofungin isapproved for the treatment of invasive aspergillosisin patients not responding toamphotericin B, and itraconazole.Adverse effects are mediated through histaminerelease: facial ﬂushing, rash, fever, and pruritus.Dose reductions are required in the presence ofmoderate hepatic insufficiency.
26 6. Pyridones 7. Thiocarbamates Ciclopirox 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 inhibitingmacromolecule synthesis.7. ThiocarbamatesTolnaftate is an antifungal agent effectivein the topical treatment of dermatophyteinfections and tinea.
27 8. Nonpolyene antibiotics Griseofulvin is an oral fungistatic agent usedin the long-term treatment of dermatophyte infectionscaused by Epidermophyton, Microsporum, andTrichophyton 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 ringwormof the beard, scalp, and other skin surfaces, 4 to 6weeks of therapy is often required.