IID 19 and 22: Antifungals Flashcards
What are the primary pathogens?
- Histoplasma capsulatum – dimorphic fungi
- Coccidioides immitis – dimorphic fungi
What are the opportunistic pathogens?
- Candida
- Aspergillus
- Cryptococcus
- Pneumocystis
- Rhizopus
What are the classes of dermatophytes?
- Trichophyton
- Microsporum
- Epidermophyton
What are some common dermatophytoses infections?
- Tinea pedis (athlete’s foot)
- Tinea cruris (jock itch)
- Onychomycosis (fungal nail infections)
- Tinea corporis (ringworm)
What do dermatophytoses do?
produce localized infections of keratinized, non-viable tissues (stratum corneum, nails, hair)
- most minor illnesses are self-limiting if cells eliminated quickly
- can become chronic in tissues that turnover slowly (ie. toenails, feet soles)
What are the 7 types of antifungal drugs?
- polyenes (AmB)
- azoles
- echinocandin (caspofungin)
- allylamides
- griseofluvin
- orotomides
- flucytosine
What is the preferred treatment for cutaneous fungal infections?
topical agents
- low risk of ADRs, localized at site of application
- very poorly absorbed
What are the topical antifungals that are reformulations of systemic drugs and what is their MOA?
- topical polyenes (nystatin) – bind to ergosterol
- topical azoles (clotrimazole, econazole) – inhibit ergosterol synthesis
- topical allylamines (terbinafine, naftifine) – inhibit ergosterol synthesis
What are the exclusively topical antifungals and what is their MOA?
- ciclopirox olanine – inhibit cellular transport
- tolnaftate – inhibit ergosterol synthesis
- undecylenic acid – unknown
- tavaborole – inhibit tRNA(leu) synthesis
- selenium disulphide – inhibit mitosis
Class I: Polyenes
- amphotericin B (fungizone)
- nystatin (mycostatin)
Polyenes – Amphotericin B (Fungizone®)
polyene macrolide antibiotic produced by Streptomyces nodosus
Polyenes – Amphotericin B (Fungizone®)
MOA
fungicidal
- binds to ergosterol in fungal cell membrane
- forms pores in membrane, altering cell permeability
- results in leakage of ions and macromolecules, changing osmolarity and eventually resulting in cell death
- selectivity results from higher affinity for ergosterol than cholesterol
Polyenes – Amphotericin B (Fungizone®)
ADME
- nearly insoluble in water, not absorbed on oral administration
- formulated for IV administration by complexing with deoxycholate
- widely distributed except to CSF
- binds to plasma proteins, accumulates in tissues
- slow elimination
Polyenes – Amphotericin B (Fungizone®)
Antifungal Spectrum
- most broad spectrum IV antifungal available
- active against almost all common invasive fungi (including many Candida and some Aspergillis species) and endemic fungi
Polyenes – Amphotericin B (Fungizone®)
Therapeutic Uses
- mainstay for treatment of serious systemic fungal infections – wide spectrum of antifungal activity, low cost, development of resistance during therapy uncommon
Polyenes – Amphotericin B (Fungizone®)
Limitations
- lack of oral bioavailability is major roadblock – new PO formulation under development
- development of nephrotoxicity is major limitation to use
Polyenes – Amphotericin B (Fungizone®)
Adverse Effects
due to interaction of AmB in mammalian cell membranes
- nephrotoxicity – reversible or irreversible
- infusion reactions – occur in most patients, fever and chills, end spontaneously in hours (reduce severity by slow infusion rate, reduce dose, pre-medication with acetaminophen, antihistamines, and/or corticosteroids)
Nystatin (Mycostatin®)
polyene macrolide antifungal agent produced by Streptomyces noursei
- too toxic for parenteral administration
- well-tolerated on topical use – available in creams/ointments for use in mucocutaneous Candida infections (particularly oropharyngeal thrush, vaginal candidiasis)
Class II: Azoles
synthetic compounds containing 5-membered azole ring
- 1st gen: imidazole – ketoconazole (nizoral)
- 2nd gen: triazole 1 – fluconazole (diflucan)
- 2nd gen: triazole 2 – itraconazole (sporanax)
- 3rd gen: triazole 3 – vorticonazole (vfend)
- 3rd gen: triazole 4 – posaconazole (spriafil)
- 3rd gen: triazole 5 – isavuconazole (cresemba)
Class II: Azoles
MOA
- fungicidal
- inhibit fungal sterol-14a-demethylase (CYP51) – ergosterol synthesis
- production and build-up of toxic alternate sterol products – membrane poisoning
- resistance (rare) is increasing mainly due to increased production or altered structure of sterol-14a-demethylase
Class II: Azoles
ADME
- major family of orally available antifungal agent
- bioavailability depends on individual formulation
- CNS availability differs for individual agent (implications on treatment of CNS infections)
- most azoles undergo extensive hepatic metabolism by hepatic enzymes before renal or GI elimination
Class II: Azoles
Therapeutic Uses
- important alternative to AmB in treatment of systemic fungal infections
- spectrum of antifungal activities is congener
Class II: Azoles
Adverse Effects
- relatively non-toxic
- most common is mild GI irritation
- may cause elevation of liver enzymes, but rarely hepatitis
Class II: Azoles
Drug Interactions
- common due to inhibition of mammalian CYP-P450s
- some congeners are likely teratogenic
Class II: Azoles
Drug Resistance Mechanisms
- increase drug efflux
- mutations of drug target (Erg11)
- increase expression of Erg11
- replacement of ergosterol with 14α-methylfecosterol (cross-resistance with polyene)
1st Gen: Imidazole – Ketoconazole (Nizoral)
- wide spectrum of adverse effects and drug interactions due to inhibition of mammalian cytochrome P450s (higher than all triazoles)
- largely replaced by newer triazoles for systemic use – only imidazole still used systemically
- used topically for superficial fungal infection
2nd Gen: Triazole 1 – Fluconazole (Diflucan)
- higher oral bioavailability, administered IV, excellent CNS penetration
- lowest adverse effects
- narrowest antifungal spectrum, but effective against many Candida species and cryptococcal meningitis
2nd Gen: Triazole 2 – Itraconazole (Sporanax)
- limited oral bioavailability, absorption increased by food and low gastric pH
- penetrates poorly into CNS
- large number of drug interactions (ie. ↓ metabolism of warfarin, omeprazole, digoxin)
- broader spectrum than fluconazole, used in systemic infections by histoplasma and blastomyce
- may be used in dermtaophytoses (including onychomycosis)
3rd Gen: Triazole 3 – Voriconazole (Vfend)
- well absorbed orally
- may result in hepatotoxicity, transient visual disturbances, skin rash
- likely teratogenic, contraindicated in pregnant women
- smaller number of drug interactions, but includes ↓ metabolism of phenytoin, warfarin, omeprazole
- broad spectrum of antifungal activity, including invasive Aspergillis (more effective and better tolerated than AmB) and as salvage therapy for infections from Scedosporium and Fusarium species
3rd Gen: Triazole 4 – Posaconazole (Spriafil)
- well absorbed orally
- may result in hepatotoxicity, ↑ risk of arrhythmia
- drug interactions with CYP3A4 and other P450 enzyme substrates (> fluconazole and voriconazole, < itraconazole)
- approved for prophylaxis against Candida and Aspergillus in immunocompromised (hematological stem cell transplant recipient w/ GVHD and patients of hematological malignancy) individual at risk of systemic infections
- broadest spectrum triazole
3rd Gen: Triazole 5 – Isavuconazole (Cresemba)
- oral or IV
- well absorbed orally w/ 98% bioavailability
- may result in hepatotoxicity and GI effects
- drug interactions with CYP3A4 and other P450 enzyme substrates (drug interactions profile is less than posaconazole, but more than fluconazole or voriconazole)
- approved for invasive aspergillosis and mucomycosis
What is the order of triazole interactions with CYP-P450?
fluconazole < isavuconazole < posaconazole < voriconazole < itraconazole
What are the topical azoles?
- include all imidazoles in addition to ketoconazole – clotrimazole, econazole, miconazole, oxiconazole
- efinaconazole is the only triazole in class
- formulations include cream, ointment, spray, and topical solutions
- widespread use as topical antifungals in: mucocutaneous candidiasis (vaginal candidiasis, oropharyngeal thrush), dermatophyte infections of skin (ie. ringworm), nails (onychomycosis)
Class III: Echinocandins
semi-synthetic cyclic peptide linked to long chain fatty acid (lipopeptides), newest class
- caspofungin
- micafungin (mycamine)
- anidulafungin (eraxis)
- rezafungin (CD101)
Class III: Echinocandins
MOA
fungicidal
- inhibit FKS-1 subunit of 𝛽(1,3) glucan synthase
- depletion of 𝛽(1,3) glucans in fungal cell wall leads to osmotic stress and fungal cell death
- selective because 𝛽(1,3) glucan is unique to fungal cells
Class III: Echinocandins
Spectrum
limited to Candida and Aspergillus species
Class III: Echinocandins
Drug Resistance
low incidences, but increasingly observed mutations of drug target FKS (𝛽(1,3) glucan synthase)
Caspofungin
ADME
- very poorly absorbed after oral administration
- only available for IV administration
- extensive hepatic and non-enzymatic biotransformation
- limited distribution to CNS
Caspofungin
Adverse Effects
- generally well-tolerated
- minor GI upset and flushing
Caspofungin
Therapeutic Uses
- active against mucocutaneous and systemic candidiasis
- approved for use in patients with invasive Aspergillis infection who failed to respond to AmB
- not useful in meningitis or endophthalmitis
Micafungin (Mycamine)
- IV administration, adverse effects rare but may include immunosuppression
- extensive hepatic enzymes dependent biotransformation
- increase serum levels of nifedipine (calcium channel blocker, use against hypertension)
- approved for use against Candidiasis
Anidulafungin (Eraxis)
- IV, minimal adverse effects
- metabolism is largely non-enzymatic (spontaneous degradation to open-ring peptide)
- no significant drug interactions
- approved for use against Candidiasis
Rezafungin (CD101)
- newest echinocandin
- topical development hampered by low chemical solubility and unstable chemical structures
- long t1/2 and superior stability, ideal properties to overcome physical limitations of other echinocandins
- approved against invasive candidiasis as systemic agent (but not in Canada), clinical trials as topical agent are ongoing
Class IV: Allylamine
highly lipophilic synthetic molecule
- terbinafine (lamisil)
- topical (terbinafine, naftifine, butenafine)
Class IV: Allylamine
MOA
fungicidal and fungistatic in some Candida species that can tolerate high squalene levels
- inhibits squalene epoxidase
- leads to accumulation of squalene (toxic) and disruption of ergosterol synthesis – acts in step of ergosterol synthesis before azoles
Terbinafine (Lamasil)
ADME
- orally available
- biotransformation mediated by multiple CYP-P450 enzymes
- accumulates in skin and nails
Terbinafine (Lamasil)
Adverse Effects
- well-tolerated, GI upset and headache occur rarely
- rarely causes idiopathic liver toxicity – patients at risk of hepatotoxicity should have liver enzymes monitored
Terbinafine (Lamasil)
Therapeutic Uses
- available in oral formulation for use in treatment of dermatophytoses, particularly onychomycosis
- treatment for 6 weeks (fingernails) to 12 weeks (toenails) results in up to 80% cure rate
- available as cream, for topical use in skin infections (ie. ringworm, jock itch)
Topical (Terbinafine, Naftifine, Butenafine)
treatment of tinea infections
Topical (Terbinafine, Naftifine, Butenafine)
- inhibit squalene epoxidase
- fungicidal against dermatophytes
- fungistatic against Candida
Other Systemic Antifungal Agents
- flucytosine (ancobon)
- griseofulvin (grifulvin)
Flucytosine (Ancobon)
MOA
- fungicidal
- anti-metabolite, fluorinated pyrimidine analog
- metabolized in fungal cells to 5-FU and interfere with DNA and RNA metabolism
Flucytosine (Ancobon)
Adverse Effects
bone marrow, liver, and renal toxicities, which could be life-threatening
Flucytosine (Ancobon)
Therapeutic Uses
only use in systemic treatment of severe candidiasis or cryptococcal meningitis, in combo with AmB
Griseofulvin (Grifulvin)
MOA
- oral fungistatic compound
- inhibits mitotic spindle assembly
- binds to keratin in newly forming skin, protecting from infection
- must be administered for 2-6 weeks (skin and hair) or up to 18 months (nails)
Griseofulvin (Grifulvin)
Adverse Effects
headache, hepatitis, increases metabolism of warfarin and phenobarbital
Griseofulvin (Grifulvin)
Therapeutic Uses
- only use in systemic treatment of mycosis of nail and keratinized tissues
- largely replaced by new antifungals (ie. terbinafine)
Additional Topical Antifungal Drugs for Cutaneous Infections
- ciclopirox olamine (loprox)
- ciclopirox 8% nail lacquer (penlac)
- tolnaftate (tinactin)
- undecylenic acid (desenex)
- tavaborole (kerydin)
Ciclopirox Olamine (Loprox)
MOA
not clear, may inhibit fungal intracellular transport
- broad spectrum fungicidal activity
- antibacterial and anti-inflammatory activity
- available as cream or lotion for tinea infections and cutaneous Candidiasis
Ciclopirox 8% Nail Lacquer (Penlac)
- for topical treatment of mild to moderate fungal nail infections
- but poor evidence against onchyomycosis
Tolnaftate (Tinactin)
MOA
inhibits squalene epoxidase (and therefore ergosterol synthesis), targeting same enzyme as allylamines
- effective in treatment of most cutaneous mycoses (fungicidal)
- not effective in those caused by Candida (fungistatic due to tolerance against squalene accumulations)
Undecylenic Acid (Desenex)
MOA
unknown
- present in human sweats
- fungistatic
- active against a variety of fungi
- used in treatment of various dermatophytoses (ie. Tinea pedis)
Tavaborole (Kerydin)
MOA
inhibits fungal tRNA(leu) synthetase (and therefore inhibits protein synthesis)
- effective in treatment of onychomycoses (fungicidal) due to agent’s ability to penetrate nail bed
- effective fungicidal activity within 5 days of topical applications
Nystatin
- mucocutaneous Candida
Topical Azoles
- mucocutaneous Candida
- dermatophyte skin infections
- onychomycosis
Ciclopirox Olamine
- mucocutaneous Candida
- dermatophyte skin infections
- onychomycosis
Tolnaftate
- dermatophyte skin infections
- onychomycosis
Topical Allylamines
- dermatophyte skin infections
- onychomycosis
Undecylenic Acid
- dermatophyte skin infections
- onychomycosis
Tavaborole
- onychomycosis
Polyenes – Systemic (1)
amphotericin B
Polyenes – Topical (1)
nystatin
Azoles – Systemic (6)
- ketoconazole
- itraconazole
- fluconazole
- voriconazole
- posaconazole
- isavuconazole
Azoles – Topical (6)
- ketoconazole
- econazole
- clotrimazole
- oxiconazole
- miconazole
- efinaconazole
Echinocandin – Systemic (3)
- caspofungin
- micafungin
- anidulafungin
Echinocandin – Topical
none
Allylamines – Systemic (1)
terbinafine
Allylamines – Topical (3)
- terbinafine
- naftifine
- butenafine
Miscellaneous – Systemic (1)
griseofulvin
Miscellaneous – Topical (4)
- ciclopirox olamine
- tolnaftate
- undecylenic acid
- tavaborole
What are some common fungi species?
- Saccharomyces cerevisiae
- Candida albicans
- Trichophyton rubrum
- Microsporum gypseum
