ANTIFUNGAL DRUGS

Prof. Dr. Hanan Hagar

MPHL - 232

FUNGAL INFECTIONS

YEAST:Cryptococcus neoformans (Cryptococcosis)Candida albicans (Candidiasis)

FILAMENTOUS FUNGI:Tricophyton.Epidermophyton.Aspergillus Microsporum.

DIMORPHIC FUNGI:Histoplasma (Histoplasmosis)

Blastomyces – (Blastomycosis)

Coccidiomyces (Coccidiomycosis)

Sporotrichomyces (Sporotrichosis)

ANTIFUNGAL DRUGS

Systemic drugs for systemic infectionsAmphotericin B FlucytosineAzoles

Oral drugs for mucocutaneous infectionsGriseofulvinTerbinafine

ANTIFUNGAL DRUGS

Topical drugs for mucocutaneous infectionsNystatinTopical azoles (miconazole-clotrimazole)Topical allylamines (terbinafine-naftifine)

I. AMPHOTERICIN B

CHEMISTRY:An amphoteric polyene macrolide antibiotic.Nearly insoluble in water.

PHARMACOKINETICS

Absorption from GIT is poor.90% is bound to serum proteinMost of drug is metabolized slowly in liver.Excretion is slow in urine, takes several days.Plasma half life is 15 daysNot dialyzable.

wide distributed in tissues except CNSonly 2-3 % of blood level is reached in CSF in meningitis (Intrathecal therapy in fungal meningitis).Drug does cross placenta. Hepatic, renal impairment and dialysis has little effect on drug concentration (No dose adjustment is required).

Conventional formulationColloidal suspension of amphotericin B + sodium desoxycholate for (I.V. injection).

Lipid formulationsLiposomal preparations (lipid associated delivery system, I.V.).

Pharmaceutical formulations

Liposomal Amphotericin B

Active drug in lipid delivery vehicles.Lipid vehicles serves as a reservoir reducing binding to human cell membrane.Given I.V.have shorter half life t½.larger doses can be used with less toxicity.More expensive

MECHANISM OF ACTION

Selective fungicide acts only against fungal sterol.Binds to ergosterol found in fungal membrane and alter permeability by forming amphotericin B-associated pores leakage of intracellular ions and macromolecules, cell death.

Combination is avid.Amphipathic characteristic.Resistance may occur.Binding to human membrane sterols may occur accounting for drug’s toxicity.

Antifungal Activity

Fungicide with the widest spectrum.Yeast:

Candida albicansCryptococcus neoformansHistoplasma capsulatumBlastomyces dermatitidisCoccidiodes immitis

Molds:Aspergillus fumigatus

Clinical Use

Drug of choice in all life-threatening mycotic infectionsfor serious fungal infection Initial induction regimen replaced later by azole drug.Cancer patients with neutropenia who remain febrile on broad spectrum antibiotics.CNS infections not responding to other drugsAmphotericin B is given by slow I.V. (0.5 – 1 mg/kg/d to a total dose of 1 –2 gm).

Intrathecal therapy for fungal meningitis is poorly tolerated.Mycotic corneal ulcers and keratitis cured by topical drops and subconjunctival injection.Fungal arthritis: intra-articular injection.Candiduria respond to bladder irrigation with no significant systemic toxicity.

Adverse Effects

infusion-related toxicityFever, chills, vomiting, muscle spasm, headache, hypotension.Decrease dose or slow the rate.Premedication: antipyretics, antihistaminic, Corticosteroids.

Cumulative toxicityRenal damage (dose-dependent, reduces renal perfusion, renal tubular injury).Anemia due to reduced erythropoietin.Common practice to administer normal saline infusion with amphotericin B.Abnormal liver function tests.

After Intrathecal therapy: seizures, neurologic damage

II. FLUCYTOSINE (5-FC)

Water soluble pyrimidine analog related to chemotherapeutic agent fluorouracil.

MECHANISM OF ACTION

Drug is taken up by fungal cells via cytosine permease and converted by cytosine deaminase to active metabolite 5-fluorouracil (5-FU) Fluorodeoxyuridine monophosphate (F-dUMP, thymidylate synthase inhibition, DNA synthesis inhibition)Fluorouridine triphosphate (FUTP, substitution for uracil, RNA and protein synthesis inhibition).

Given orally, well absorbed.Poor protein binding.Wide distribution including CNSEliminated by glomerular filtration.Half life 3-4 hRemoved by hemodialysis.TDM is important in renal insufficiency (50-100 mg/ml).

Pharmacokinetics of flucytosine

narrower spectrum of activity than amphotericin B.Restricted to: some Candida species, Cryptococcus neoformans, molds causing Chromoblastomycosis.Not used as single agent.Resistance develops rapidly.Synergism between Fluocytosine and Amphotericin B both in vivo and in vitro.Synergism between fluocytosine and azoles in vitro

Spectrum of activity of flucytosine

Use is confined to combination therapyFluocytosine and Amphotericin B for Cryptococcus meningitisFluocytosine and itraconazole for Chromoblastomycosis

Uses of flucytosine

Adverse effects of flucytosine

Toxic effects due to fluorouracil formation (by gut flora).Bone marrow depression, anaemia, leukopenia, thrombocytopenia.Liver enzymes abnormalities.Toxic enterocolitis.Narrow therapeutic window

III. AZOLES“Synthetic fungicides”

I. IMIDAZOLES:KetoconazoleMiconazole (Topical)Clotrimazole (Topical)

II. TRIAZOLES:ItraconazoleFluconazoleVoriconazole

Mechanism of Action:

Interferes with cell membrane permeability by decreasing ergosterol synthesis via inhibition of fungal cytochrome P450 (14 α-demethylase) required for conversion of lanosterol to ergosterol.Have greater affinity to fungal cytochrome than human.

Mechanism of Action

Imidazoles have lesser degree of specificity than traizoles.Imidazoles have more drug interactions and side effects. Resistance is common.

Mechanism of Action

Spectrum of activity

Broad spectrum of activity:Candida. Cryptococcus neoformansEndemic mycosis (Blastomycosis, histoplasmosis)Dermatophytes.Asperigllus infection (voriconazole & itraconazole)

Adverse effects

Relatively non toxicMinor GIT upsetLiver enzymes abnormalitiesDrug interactions (varies according to drug)

Ketoconazole

First oral azole.Less selective for fungal P450 than newer drugs.Has greater propensity to inhibit mammalian cytochrome P450Best absorbed at low gastric pHUseful in treatment of mucocutaneous candidiasis

Adverse effects of ketoconazole

Interferes with biosynthesis of adrenal and gonadal steroid hormones leading to:

Gynaecomastia.Infertility.Menstrual irregularities.Has narrow therapeutic range.Drug interactions

Important Drug Interactions With Ketoconazole:

plasma levels of oral anticoagulants, oral hypoglycemic, phenytoin, cyclosporine.Enhanced arrhythmogenic effect of antihistamine, astimazole and terfenadine.Cimetidine increase gastric pH thereby interfere with absorption of ketoconazole. ↓ plasma level.Rifampin increase hepatic metabolism of the azole. ↓ plasma level.

Fluconazole

oral, I.V. route. High oral bioavailability Good penetration to CSF.The least microsomal inhibitory effect. Lack of endocrine effect.Renal elimination (dose should be ↓ in renal impairment)

The widest therapeutic window which permits more aggressive dosing.

Drug of choicetreatment of esophageal & oropharyngeal candidiasistreatment of cryptococcal meningitis in immunodeficient patients.No activity against aspergillus

Fluconazole

Itraconazole

Oral-IVAbsorption increased by food-low pHCyclodextran enhance bioavailabilityInhibits cyt P450 (lesser than ketoconazole)Drug interactions is less than ketoconazoleReduced bioavailability with rifamycinsNo effect on mammalian steroids synthesis

Itraconazole

Poor CSF penetrationAzole of choice in systemic infections due to dimorphic fungi (histoplasma, blastomyces, sporothrix)Drug of choice in treatment of dermatophytosesactive against aspergillus (replaced by voriconazole)

Voriconazole

The newest triazole , Oral- IV Well absorbed, (90% bioavailability)Less protein binding than itraconazole Inhibition of P450 is lowThe most potent azoleBroader spectrum.

Voriconazole

Similar to itraconzole in spectrumExcellent activity against candida, dimorphic fungi and aspergillus infections (the drug of choice for invasive aspergillosis)Rash, elevated hepatic enzymes, visual disturbances

Oral, IV

Oral, IV

Oral, IV

Oral

Formu-lation

Hepatic6lowHighthe drug of choice for invasive aspergillosis

Voriconazole

Renal22–31GoodHighcryptococcal meningitiscandidiasis

Fluconazole

Hepatic24–42lowVariablethe drug of choice for dermatophytoses & dimorphic fungi

Itraconazole

Hepatic7–10lowVariablemany sideeffects

Ketoconazole

Elimination

t 1/2hour

CNS conc

Absorption

Uses

Pharmacologic properties of systemic azole drugs

Echinocandinsglucan synthesis inhibitors

The newest classActive against candida and aspergillus but not Cryptococcus neoformans.Caspofungin, micafungin, anidulafunginblocks the synthesis of a major fungal cell wall component, beta (1, 3) glucans leading to disruption of cell wall & cell deathused in mucocutaneous candida infections

Mechanism of action

block fungal cell wall synthesis by inhibiting the enzyme 1,3-beta glucan synthase depletion of glucan polymers in the fungal cell weak cell wall unable to withstand osmotic stress

cell death

Echinocandins

Minor GIT side effects – some drug interactionsCaspofungin elevated liver enzymes if combined with with cyclosporine (combination should be avoided)Micafungin cyclosporine, sirolimus, nifedipine Anidulafungin histamine release upon IV infusion

Esophageal &invasive candidiasis

Mucocutaneous candidiasis

prophylaxis in bone marrow transplants

Mucocutaneous candidiasis

Invasive aspergillosis

Febrile neutropenia

Uses

histamine release upon IV infusion

elevated plasma levels of cyclosporine, sirolimus, nifedipine

elevated liver enzymes with cyclosporine

Candida, aspergillusCandida, aspergillusCandida, aspergillus

24-48 h Longest11-15 h9-11 hT1/2

IV onlyIV onlyIV onlyAdminist

anidulafunginmicafungincaspofungin

Oral drugs formucocutaneous infections

GriseofulvinTerbinafine

I. GRISEOFULVIN

Very insoluble fungistatic drug derived from Penicillium. Orally, Absorption promoted by fatty meal.biliary excretionOral formulation

Micronized-Ultramicrosized

Mechanism of action

Griseofulvin inhibits fungal mitosis by disrupting the mitotic spindle through interaction with polymerized microtubulesOnly used in systemic treatment of dermatophytosis. It is deposited in newly forming skin where it binds to keratin precursor cells, protecting the skin from new infection.

GRISEOFULVIN

Skin and hair infections (2-6 weeks).Nail infection (longer periods, months)Nausea, diarrhea, headache, skin eruptions and photosensitivity, serum sickness like syndrome, hepatitis.Griseofulvin is microsomal inducer (decrease anticoagulant effect of Warfarin)

II. TERBINAFINE

Synthetic allylamine available in oral formulation- cream.Like griseofulvin, is a keratophilic medication but has fungicidal action.

Mechanism of terbinafine

Acts by interfering with ergosterol biosynthesis like Azole drugs through inhibition of fungal enzyme squalene epoxidase → ↑ squalene which is toxic to organism.Used in treatment of dermatophytosis especially Onychomycosis (more effective than griseofulvin or itraconazole)

Terbinafine cream is effective for treatment of Tinea cruris and Tinea corporis

Topical antifungal drugs

Topical azoles (clotrimazole, miconazole)Creams, solution, lotion, vaginal suppositoriesOral thrushVulvovaginal candidiasisDermatophytic infections (tinea corporis,

tinea pedis, tinea cruris).absorption is negligible, rare adverse effects

Topical antifungal drugs

Topical ketoconazole cream, shampoo Treatment of seborrheic dermatitis, pityriasis versicolor

Topical allylamines (terbinafine- naftifine)Creams, gelDermatophytic infections (tinea corporis, tinea cruris).

Nystatin

Polyene macrolide antibioticToo toxic for parenteral administrationCreams, ointment, suppositoriesNot absorbed to a significant degree from skin, mucous membrane, GITLittle toxicityOral thrush - Vaginal candidiasis