Antifungals 2011

7/31/2019 Antifungals 2011

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Antifungal Drugs

Dr. Meera Ababneh, PharmD, PhD.


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Antifungal Overview


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Fungal Infections

Superficial/cutaneous Dermatophytosis (tinea, ringworm) Candidiasis (yeast)

Systemic

Aspergillosis

Blastomycosis Coccidiomycosis

Histoplasmosis Paracoccydioidomycosis Sporotrichosis


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Treatment of Dermatomycosis

Ringworm, athletes foot, jock itch

treatment choice may depend on organism,location, level of inflammation, immune

status, etc


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Systemic Therapy

Oral medications may be necessary for:

extensive infections

tinea capitis

immuno-compromised

folliculitis

Onychomycosis

Recurrent/chronic infections


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Antifungal Drugs

ALLYLAMINE

Terbinafine

ECHINOCANDINS

Caspofungin, Micafungin, anidulafungin AZOLES

Ketoconazole, Itraconazole, Fluconazole,

Voriconazole, Posaconazole

PYRIMIDINE ANALOG Flucytosine

POLYENE MACROLIDE

Amphotericin B


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Terbinafine

Allylamine, keratophilic and fungicidal

Pharmacokinetics:Administration oral or topical

Highly protein bound but widely distributed

high concentrations persist in the stratumcorneumhair and nails

Disposition -primarily hepatic metabolism


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Terbinafine

Contraindications (for oral admin); Reduce dose w/ impaired hepatic clearance

Preg cat B, but not during lactation

Interactions (for oral admin): Inhibits CYP 2D6 numerous interactions

Other Interactions

Increases clearance of cyclosporine Rifampin doubles terbinafines clearance rate

Cimetidine decreases terbinafine clearance


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Terbinafine

Adverse effects - headache/dizziness and

GI effects most common

Hepatic injury - rare, but should monitor LFT

Mild to serious skin reactions (rare)

Transient lymphopenia and neutropenia (rare)

Neuropsychiatric effects in pediatrics (rare)


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Indications

superficial dermatophytic

infections(topical)

onychomycosis (oral)


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Itraconazole

Moderate spectrum triazole

Administration: Oral - decreased pH favors absorption

Take capsule w/ food, solution w/o

Avoid gastric acid inhibitors

Distribution -good except CNS Disposition - hepatic metabolism; long t1/2


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Itraconazole

Contraindications/Interactions: Patients w/ heart failure

Liver disease

Preg cat C

Potent inhibitor of CYP 3A4 also inhibits P-gp

numerous interactions

Avoid drugs which increase QT interval


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Itraconazole

Adverse effects:Generally well tolerated GI distress

Headache/dizziness

Cardiovascular effects Increased hepatic transaminase activity in 5-

10%; serious hepatic damage (rare)

Peripheral neuropathy, visual disturbances,hearing loss, tinnitus (rare)


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Fluconazole

Triazole, broad spectrum

PK:

Administration: Oral - not pH or food dependent; bioavailability

90%

Intravenous

Distribution

Very good, including CNS; 50-90% of blood levels

Disposition - Primarily renal; long t1/2 -30 h


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Fluconazole

Indications:

Candidiasis (except krusei)

Cryptococcosis: Fluconazole is the best azole

agent for fungalmeningitis because of highCSF levels


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Fluconazole

Contraindications / Interactions:

Preg cat C (teratogenic in animals)

Inhibits CYP450 enzymes decreased clearance of

some drugs Rifampin increase fluconazole clearance

Avoid drugs which prolong QT interval

Adverse effects: generally well tolerated

GI effects & headache most common

Increased hepatic transaminases

QT prolongation and torsades de pointes (rare)


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Griseofulvin

Binds to microtubules, disrupts mitosis

Long term therapy required 2 4 wks for skin infection

4-6 wks for hair/scalp 4 8 wks foot infections

3 4 months for fingernails

6+ months for toenails

Oral administration Microparticles

Enhance with fatty food


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Griseofulvin

Adverse effects ---> secondary course of

treatment

Headache: 15% incidence

Hypersensitivity reactions

Teratogenic and carcinogenic in animals

Itraconazole or Terbinafine preferred


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Topical Treatment ofDermatophytosis

Antifungal creams containing: Clotrimazole

Miconazole

Ketoconazole

Terbinafine

Undecylenic acid and salts (Desenex: Zn salt)

Tolnaftate(Tinactin) -T. pedis, T. cruris

Selenium sulfide suspension (Selsun) -forseborrhaic dermatitis of scalp

Benzoic and salicylic acids (Antinea)

Potassium iodide -also used for cutaneous

sporotrichosis


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Superficial Candidiasis


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Clotrimazole

Topical product

Variety of preparations - cream, lotion, solution,

oral lozenge (use appropriate prep!) MOA: typical of azoles

PK: Poor penetration beyond the skin,

5-10% following intravaginal use


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Clotrimazole

Contraindications: Vaginal - Preg Cat B; not


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Nystatin

Polyene macrolide

Pharmacokinetics -not absorbed from theGI tract

Adverse effects -too toxic for systemic use

Indications Mouth (oral Candidiasis [thrush])

Skin and mucous membranes - Intravaginal (2week course)

Lower GI tract (oral administration)


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Broad Spectrum Antifungal Drugs forSuperficial Candiasis

Cutaneous

Topical azole treatment (clotrimazole [GyneLotrimin], miconazole [Monistat])

Systemic azole treatment for extensiveinfections, immunocompromised, folliculitis

Vaginal Candidiasis:

Topical Azoles (butoconazole, clotrimazole,miconazole, tioconazole, terconazole)

Systemic treatment fluconazole,itraconazole


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Broad Spectrum Antifungal Drugs forSuperficial Candiasis

Oral Candidiasis:

clotrimazole lozenges [Mycelex troche]

nystatin mild

oral fluconazole for moderate to severe


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Compounds for

Deep/Systemic Disease


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Voriconazole

Triazole w/ spectrum slightly better thanitraconazole

PK:

Administration -oral (96% bioavailability) and IV (betacyclodextran vehicle)

Distribution - generally good, --> CSF

Dispositionprimarily metabolizeddose dependent t 1/2

Indications invasive aspergillosis


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Voriconazole

adverse effects

reversible visual disturbances (30%)

increased hepatic transaminase activity

photosensitivity

Interactions -many interactions involving

altered metabolism (Cyp3A4 inhibitor)


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Posaconazole

Triazole, potent broad spectrum antifungal

PK: Administration - oral - greatly increasedby high fat

meal

disposition -fecal elimination of unchangeddrug andmetabolites

Indications Prevention of Candida and Aspergillus in severely

immunocompromised patients

Non responsive aspergillosis and candidosis


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Posaconazole

Contraindications / Interactions Proton pump inhibitors, H2 receptor blockers and

antacids (impair absorption)

Inhibits CYP3A4

Drugs which prolong QT interval

Adverse effects- generally well tolerated GI effects, fatigue & headache most common

increased hepatic transaminase activity

QT prolongation and torsades de pointes (rare)


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Echinocandins

Inhibit synthesis of 1-3-beta-D-glucan in

cell wall

No mammalian equivalents

Pharmacokinetics

Administration -IV

Disposition -redistribution and slow hepatic

metabolism, fecal elimination


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Echinocandins

Contraindications / Interactions Drug interactions - relatively few identified

metabolism increased by rifampin, dexamethasone, others

levels increased by cyclosporin

Caspofungins decrease tacrolimus levels

Decrease dose w/hepatic impairment, but not renal

Adverse effects -generally well tolerated Occasional effects due to histamine release (rash,

itching,urticaria, flushing, hypotension) fever Nausea and vomiting


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Indications Capsofungin

Aspergillosis-invasive

Severe Candida infections(hospitalized patients)

Anidulafungin esophageal candidiasis

Candidemia and other complicated candida infections(intra abdominal abscess, peritonitis)

Micafungin esophageal candidiasis

prophylaxis against Candida infections in patientsundergoing hematopoietic stem celltransplantation

A h i i B


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Amphotericin B: Deoxycholate(Fungizone) or liposomal (Amphotec, Albecet,AmBisome) preparations

PharmacokineticsAdministration

IV - most common, deoxycholate suspension or

liposomal preparations Local application

Distribution: Wide except for CSF

>90% protein bound

Binds to cell membrane and tissue lipids Reason for liposomal preps - alternate binding site to

host tissue


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Amphotericin B

Pharmacokinetics

Disposition:

Biphasic:Initial (distribution)

T 1/2 = 24 Hrs

Elimination: T 1/2 = 15 Days

Metabolism and urinary excretion

Excreted in urine several weeks afteradministration stops


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Amphotericin B

Therapeutic uses:

Major treatment for most rapidly

progressing or severe systemic mycosesdespite toxicity

Used as induction therapy

Used for non-responsive infections

Well characterized in pregnant patients


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Amphotericin B

Adverse effects:

Infusion related - pretreat w/ NSAID,antihistamine or cortisone and meperidine

Fever and Chills Vomiting

Headache

Hypotension

Renal toxicity: deoxycholate form 80% of patients azotemic

Preload w/ sodium to px/minimize

Documents

Antifungals 2011