Antifungal Agents Flashcards
Compared to bacteria, fungi have
Different ribosomes
Different cell wall components (chitin, mannoproteins and glucans)
A nuclear membrane
Control of mycotic infections
Immunization is not usually effective
Control involves IV amphotericin B, flucytosine, azoles and nystatin
In some cases surgical removal of damaged tissue
Prevention limited to masks and protective clothing to reduce contact with spores
Except for _________________ and _________________, all currently available antifungals target the cell membrane
Flucytosine; griseofulvin
Azoles
Interfere with ergosterol synthesis by targeting lanosterol demethylase enzyme, leading to defective cell membranes through accumulation of toxic sterol products; used to treat a variety of systemic and localized fungal infections
All are synthetic, show broad activity towards years and molds (no antibacterial action), orally active or topical, and fungistatic or fungicidal
Imidazoles - ketoconazole, miconazole and clotrimazole
Triazoles - fluconazole and itraconazole
Imadazoles
COMET - K
Clotrimazole Oxiconazole Miconazole Econazole Tioconazole Ketoconazole
Triazoles
FIT VIP
Fluconazole Itraconazole Terconazole Voriconazole Isavuconazole Posaconazole
Echinocandins
MAC
Micafungin
Anidulafungin
Caspofungin
Allylamines
ANT
Amorolfin
Naftifine
Terbinafine
Clotrimazole
Topical imidazole (cream, ear drops) - OTC
Troche - throat lozenge
Treats vaginal yeast, ringworm, athlete’s foot, jock itch and thrush
Side effects include skin irritation, rash, hives, burning, itching, redness, est.
Ketoconazole
Imidazole
Tablet, cream, shampoo
Oral administration, requires low pH for absorption
Numerous dose-limiting side effects: hepatotoxic, teratogenic, GI disturbances, disruption of mammalian steroid hormone biosynthesis
Largely replaced by the newer triazoles
Fluconazole
Oral or IV Triazole - good absorption and distribution; also for topical use
Oral and esophageal candidiasis in AIDS patients
Cryptococcal meningitis
Better tolerated than ketoconazole
Resistance is common, but usually limited to AIDs patients and after long-term therapy
Potential adverse effects: rash, nausea, hepatotoxicity
Itraconazole
Oral Triazole
Similar to ketoconazole in structure but can’t form the same toxic metabolites
Better specificity for fungal cyp450, decreasing toxicity
Broader spectrum than fluconazole, but not as well tolerated as fluconazole
Often drug of choice for non-life-threating mycoses
99% protein bound; no cerebrospinal fluid penetration
Many potential side effects
New Generation Triazoles
Some have excellent in vitro activity against a wide variety of fungal pathogens
MIC values lower against most Candid spp.
Have in vitro activity against Aspergillus sp. that is comparable or better than that of amphotericin B and itraconazole
Voriconazole, Posaconazole
Voriconazole
New generation triazoles
Approved for acute invasive aspergillosis and salvage therapy for several other rare mycoses
Outperformed amphotericin B in trials
IV or oral
Side effects include visual disturbances and increased liver enzymes
Posaconazole
New generation triazole
Similar to itraconazole but better activity and broader spectrum; may cause more serious side effects
Side effects include fever, diarrhea, nausea, increased liver enzymes
Oral only; slow absorption (3-5 hours) and has a long half life (35 hours)
Used to treat invasive infection of Candida, Mucor, and Aspergillus in immunocompromised patients
Azole resistance
The broad use of fluconazole and other azoles resulted in isolated Candida species resistant to azoles
Three types of drug-resistance:
(1) replacement of initially susceptible species by intrinsically resistance species of Candida
(2) Replacement of an initially susceptible Candida strain by a more resistant strain of the same species
(3) Development of resistance in a single strain of Candida species
Mechanisms include decreased uptake or increased efflux; altered sterol C14 demethylase or other ergosterol biosynthetic enzymes; amplification of genes encoding for target enzymes
Fungicidal polyenes
Bind ergosterol forming drug-lipid complexes which intercalate into the fungal cell membrane to form a membrane-spanning channel
This causes cellular ions to leak out of the cell, destroying the proton gradient and culminating in osmotic cellular lysis
Amphotericin B
Polyene antifungal; polyketide natural product of Streptomuces sp; all have 4-7 conjugated double bonds on one side and multiple hydroxyls on the other side; has free carboxy on the macrolide and is modified with an amino sugar
Creates an amphoteric molecule
Most potent antifungal for systemic infections but is highly nephrotoxic (80% of patients show sign of kidney damage; toxicity is dose dpenedent and usually transient if renal function was normal before therapy)
Administered IV
Polyenes
NAN
Natamycin
Amphotericin B
Nystatin
Echinocandins
Act as noncompetitive inhibitors of (1,3)-B-d-glucan synthase (encoded by FKS1) and therby cause a loss of cell wall integrity and severe cell wall stress
Caspofungin
Echinocandin - lipopeptide antifungal natural product
For treating invasive aspergillosis, also effective towards Candida
Given IV - good solubility to H20 | Long t1/2 allows once a day dosing | Metabolized by acetlyation
Minimal side effects
MOA: Inhibit 1,3,B-glucan synthase, blocking assembly of fungal cell wall; no Cryptococcus neoformans activity due to thick capsule
MOR: Rare but substitutions in FKS1P subunit of 1,3-B-glucan synthase confer reduced susceptibility
Micafungin
Echinocandin
Approved for candidiasis in person undergoing bone marrow transplant and for esophageal candidiasis
Braod spectrum against Candid spp., including azole-resistant C. albicans
Anidulafungin
Echinocandin
Semisynthetic - has echinocandin B nucleus with modified terphenyl tail
Approved for esophageal candidiasis, candidemia and peritonitis due to candida infection
5-fluorocytosine (Flucytosine)
Synthetic | only oral | resistance is common in monotherapy - usually combined with amphotericin B - for severe systemic fungal infection
MOA: Interferes with fungal protein and DNA synthesis; requires metabolic activation
Side effects: Hepatotoxicity, bone marrow depression
Griseofulvin
Natural product taken orally for dermatophytic infections of hair and nails
MOA: Inhibits fungal mitosis by preventing separation of the chromosomes
Effect is only fungistatic; poor bioavailability which can be increased through micronization of dose
Side effects: Headache, rash, GI pain
Allylamines
Inhibit squalene epoxidase (first step in synthesis of ergosterol)
Terbinafine, Butenafine
Terbinafine
Effective topically or systemically, mostly for nail fungus
Inhibits ergosterol biosynthesis
Topical squalene epoxidase inhibitor
Butenafine
Active vs dermatophytes and C. albicans
Achieves high skin concentrations and remains in skin tissue for prolonged periods
Exerts anti-inflammatory as well as antifungal activity in vivo; beneficial in dermatophytic infections that are accompanied by a marked inflammatory reaction in the infected tissue
Better fungicidal activity than terbinafine
Tolnaftate
Thiocarbamate
Cream, powder, spray, liquid aerosol
Broad spectrum but no anticandida activity
Used topically for athlete’s foot and jock itch
MOA: inhibits ergosterol biosynthesis (target is squalene epoxidase)
