Antifungal Agents Gillian Tufts DNP FNP Fungal Infections

Antifungal Agents Gillian Tufts DNP, FNP

Fungal Infections • • Blastomycosis Aspergillus Histoplasmosis Mucor Coccidiodomycosis Cryptococcus Dermatophytes Candida albicans

Fungal Infections: the Drugs • • • Amphotericin B Griseofluvin Flucytosine Azoles Allylamines Echinocandins

Azoles • 2 classes • Imidazoles • Ketoconazole • Miconazole (topical) • Clotrimazole (topical) • Butoconazole (topical) • Triazoles • Fluconazole • Itraconazole • Voriconazole • Posaconazole • Terconazole (topical)

Azole: MOA • Deplete cell membrane of the steroid compound ergosterol • Inhibits enzyme in fungal CYP system • See decreased fluidity of cell membrane and increased toxic accumulation • Eventual cell death

Azoles • Ketoconazole (Nizoral) • First of the azoles • Similar spectrum • Not used much currently

Azoles • Fluconazole (Diflucan) • Spectrum: Candida, Cryptococcus • Resistance with C. glabrata, C. krusei • Alternate: Blastomycosis, Histoplasmosis • Alternate: Onychomycosis • Side effects: generally well tolerated, N/V, headache • ADR: LFT elevation

Azoles • Itraconazole (Sporonox) • Spectrum: Histoplasmosis, Blastomycosis, Paracoccidoioidomysosis, Coccidiodomycosis • Alternate in Cryptococcosis, Asperigillosis • Onychomycosis (dermatophyte) • Side effect: GI complaints, headache • ADRs: LFT elevation (baseline & q 4 -6 wk), hypokalemia • Drug-drug interactions extensive

Azoles • Voriconazole (Vfend) • Spectrum: Candida species, Aspergillus, Fusarium • Including C glabrata and krusei • Does penetrate BBB • Side effects: relatively well tolerated, transient visual disturbances, GI complaints • ADRs: LFT elevation, QT prolongation • Pregnancy category D • Potential for drug-drug interaction

Azoles • Posaconazole (Noxacil) • Spectrum: Candida species and Aspergillus • Especially in immunocompromised individuals, ie mucormycosis • Side effects: relatively well tolerated, GI complaints • ADRs: LFT elevation, QT prolongation • Drug-drug interactions

Pharmacokinetics of Azoles Drug (azole) Absorption Distribution Metabolis (PB) m Excretion Ketocon Likes acid medium 99% Hepatic Bile mostly CYP inhibitor Sm amt urine Flucon ~ 90% 10% Minor hepatic ~ 80% urine unchanged Mod inhibit CYP 3 A 4, 2 C 9 Itracon ~ 50% ~ 99% By 3 A 4 < 20% stool unchanged 3 A 4 inhibitor Voricon > 90% 58% Phase II hepatic < 2% urine unchanged Mod 2 C 19 Min 2 C 9, 3 A 4 99% Phase II hepatic Mostly stool, little urine 3 A 4 inhibitor Posacon Food increases Drug-drug interaction

Nystatin • MOA • Similar action to amphotericin B: binds with fungal membrane sterols allowing content leakage and cell death • Poor absorption via intact mucous membranes • Typically used in oral or gastrointestinal fungal infection • Avoid taking at meal times • Prolong medication contact at mucosa • GI distress

Terbinafine (Lamisil) • Spectrum: Dermatophyte, candidiasis • MOA, same as the azoles but different site in pathway • Naftifine (naftin) topical only • Tends to accumulate in the skin, nails, fat tissue • Generally well tolerated: GI SEs, funny taste, transient mild skin itching • ADRs: hepatotoxicity, rarely serious skin rash

Griseofulvin • MOA: though to work through disrupting the microtubule function. This is part of mitosis, alters this process • Spectrum: Dermatophytes • Absorption increased by food, bioavailability up to 75%, also increased with new formulations: • Micro-sized and ultra-microsized • Deposited into keratin precursor cells, only small found in other tissues • HA, N/V, GI, phototoxicity, disulfiram reaction • Drug interactions: Inducer, warfarin, oral contraceptives

Yeast Infections Pharmacologic Management

Oral Therapy for Candidal Thrush Mild infection • Nystatin • 5 cc swish/swallow qid for 14 days • Clotrimazole (10 mg troches) • Dissolve 1 troche po 5 xday -- Do NOT chew! • GI distress Refractory / more serious infection • Avoid Nystatin or Clotrimazole for esophagitis • Fluconazole • 200 mg po day 1, then 100 mg po qd x 2 -3 wks • Children: generally 3 -12 mg/kg/day (1 dose tdouble amount) • Dose according to Cr. Cl • Check regimen for Rx: Rx • Itraconazole • 100 mg po qd x 2 -3 wks

Vulvovaginal Candidiasis: Treatment Options OTC Azoles • Butoconazole (Femstat 3™) • Clotrimazole (Gyne-Lotrimin™, Mycelex™) • Miconazole (Monistat 7™) • Tioconazole (Vagistat-1™) Prescription Azoles • Clotrimazole vaginal tablets • Miconazole vaginal suppository (Monistat. TM) • Terconazole (Terazol™): 3 or 7 day cream or suppository • Fluconazole oral tab: 150 mg po x 1, may repeat in 3 -5 d

Tinea Infections Pharmacologic Management

Tinea Pedis • Common dermatophyte infection • Signs/symptoms • Itchy, macerated skin between toes • Large blisters, deep fissures • Topicals applied qd to bid • Clotrimazole • Terbinafine • Tolnaftate 1% • Miconazole • Treat for 4 weeks • Nonpharmacologic

Tinea corporis / cruis • Tinea corporis or “Ringworm” • Appearance with defined margins • Hot humid climates • Tinea cruris • Affects groin/thighs/perineal areas • Warm/moist areas • Exacerbated by obesity or tight fitting clothes • More common in males • Treatment • Same topical agents as Tinea pedis (4 weeks)

Fungal Nail Infections • Tinea unguium or onychomycosis • Topical therapy not effective • Achieve fungicidal concentration within nail • Toe nail thickness > finger nail thickness • Terbinafine • Itraconazole

Fungal Nail Infections • Griseofulvin: cure rates < 20%, relapse 60% • Terbinafine 250 mg daily • Fingernail for 6 weeks • Toenail for 12 weeks • Itraconazole • 200 mg daily for 8 weeks • Pulsatile dosing: 200 mg BID for 1 week/month for 3 mos • Fluconazole (being studied) • 300 mg po q wk x 3 -6 mo (fingers) • 6 -12 mo (toes)

Tinea capitis • Topical do not work • Treat for several weeks • Griseofulvin: 500 mg qd x 4 -6 wks; 10 -20 mg/kg/day ‘til hair regrows (~ 6 -8 wks) • Terbinafine 250 mg/day for 4 to 8 weeks; kids 125 mg/day • Itraconazole: 3 -5 mg/kg/d x 4 wks • Fluconazole: 8 mg/kg q wk x 8 -12 wks

Systemic Antifungal Agents • Polyene Macrolides: Amphotericin B (IV) • Pyrimidine: Flucytosine (PO) • Echinocandins • Caspofungin (IV) • Anidulafungin (IV) • Micafungin (IV) • Azoles • Voriconazole (IV, PO) • Posaconazole (PO)

Amphotericin B • Binds with ergosterol, forming complexes = pore formation and leakage • Spectrum: Candidemia, Aspergillosis, Blastomycosis, Histoplasmosis, Coccidiodes, Cryptococcosis, Fusariosis, Mucormycosis, Paracoccidiodes • New formulation with lipid carriers to reduce infusion reactions (fever, rigors, chills) • Lipid-based formulation: amphotericin colloidal dispersion, amphotericin lipid complex, liposomal amphotericin

Amphotericin B • All given IV • All are highly protein bound, > 95% • Minimal metabolism • Little excretion by kidneys, <20% conventional, < 5% lipid forms • Fever/rigid less with liposomal amphotericin B • All are nephrotoxic, less with lipid forms • No hepatoxicity with amphotericin B, rarely with others

Flucytosine • Impairs fungal DNA production • Useful in candidia and cryptococcus • Oral agent with good bioavailability • Little protein binding • ~ 80% renal excretion • GI side effects

Echinocandins • Newer class of antifungal • Caspofungin • Micafungin • Anidulafungin • MOA: inhibits enzyme needed for synthesis of glycan, essential component of fungal cell wall • Spectrum: Candidiosis, aspergillus • Poor against histoplasma, blastomyces, coccidioides, cryptococcus, trichosporon

Echinocandins • All 3 are large molecules, poor bioavailability = IV administration • All are highly protein bound • None are metabolized by CYP P 450 system • Excretion, negligible unchanged in urine, metabolites in feces and urine • Capsofungin has indication in children 3 mos to 17 yrs • Data available with others