Antifungal Agents Flashcards
Fungi
Eukaryotic organisms that live as saprophytes or parasites. Resistant to ABX.
Termed Mycoses
Types of Fungi
Superficial- skin, nail/hair, mucous membranes
Systemic- deep tissues, organs
3 Groups of fungi that cause disease
Molds
True yeast
Yeast-like fungi
Fungal pathogenicity results from
Mycotoxin production
Allergenicity/inflammatory reactions
Tissue invasion
Opportunistic fungal infections are important causes of disease in immunosuppressed
Route selection for superficial and cutaneous infections
Selection of anti fungal therapy should be based on extent and type of infection
Superficial and cutaneous- usually topical
Follicular, nail, or widespread- systemically
Vehicle selection
Ranking the drying effect of formulations
gel>lotion/solutions/cream/ointment
Powders are used only as adjuncts
Systemic fungal infections
Tx depends on stage and severity
Choices revolve around the same drugs for all systemic fungal infections
Risk factors include- immunosuppression (HIV, CA chemo, or steroids), diabetes, TPN
Antifungal Drugs
Polyene antibiotics Imidazole antifungals Triazole antifungals Other antifungal agents Tx can last weeks to months and is more effective on the skin than the nails.
Amphortericin B
Polyene ABX
Naturally occuring polyene macrolide antibiotic produced by streptomyces nodosus
MOA- Bind to ergosterol in the fungal cell membrane and form pore-> leak “-cidal”
Selective toxicity
Resistance- infrequent due to decreased ergosterols in membrane
Nystatin
Polyene ABX
MOA- Bind to ergosterol in the fungal cell membrane and form pore-> leak “-cidal”
Selective toxicity
Active transport mechanism
Amphortericin- pharmacokinetics
ROA- IV
Liposomal preps less renal and infusion toxicity
Amphortericin indications and ADRS
Broad specturm anti-fungal used in potentially fatal systemic infections
-Candida albicans, histoplamsa capsulatum, cyrptococcus neoformans, coccidoices immites, blastomyces dermatitides, aspergillis
ADRs- HYPOTENSiON, anemia, nephrotoxocity, thrombophlebitis, fever/chills, allergic reactions
Nystatin-pharmacokinetics
Topically as a cream
Vaginal troches
Suspension deliver drugs to oral mucosa
Nystatin- indications and ADRS
Used to supress candidiasis on the sin and mucous membranes (oral&vaginal)
ADRs- N/V/D
Flucytosine (Ancobon)
Polyene ABX
MOA- inhibits synthesis of fungal pyrimidines
ROA- PO
Indications- in combination w/ amphoB to treat systemic candiasis and cryptococcuss meningitis
ADRs- N/V/D, rare hepatotoxicity and seen more often is thrombocytopenia, neutropenia, bone marrow suppression
Griseofulvin (Fulvicin)
Polyene ABX
MOA- binds to fungal microtubules disrupting mitotic spindles “-static”
Indications- DOC in kinds for wide spread dermatophyte or intractable dermatophyte infection where topical agents have failed. No longer for dermatophyte infection of nails
ADRs- fever, HA, mental confusion, rashes, GI disturbances.
Griseofulvin (Fulvicin)- drug interactions
P450 inducer- barbiturates, OCP, warfarin
High fat meals increase absorption
Potentiates intoxicating effects of ETOH
Ketoconazole (nizoral)- MOA
Azoles Imidazoles
MOA- broad spectrum: histoplasma, blastomyces, candida, coccidioides, NO ASPERGILLUS
Predominately fungistatic but can be -cidal depending on dose
Inhbits C-14-alpha-demethylase (P450 enzyme) disruptong the membrane
Also inhibits human steroid synthesis leading to decreased testosterone and cortisol production.
Ketoconazole (nizarol)- Pharmacokinetics and ADR
PO-requires gastric acid for dissolution
Penetration into tissues limites, effective in tx of histoplasmosis in lung, bone, skin, soft tissue
Doesn’t enter CNS
ADRs- N/V, anorexia, endocrine effects such as gynecomastia, impotence, irreg menses, teratogenic due to endocrine effects
Ketoconazole (nizarol)- Drug interactions and resistance
P450 INHIBITOR
Resistance- mutation of p450 enzyme leasts to decreased azole binding
Ability to pump azole out of the cell.
Azoles Imidazoles
Clotrimazole (Lortimin, mycelex)
Miconazole (Monostat, desenex)
Terconazole (terazol)
Butoconazole (Femstat3)
Topical only; severe toxicity when used IV
MOA and spectrum same as ketoconazole
Topical use w/ contact dermititis, vulvar irritation, edema
TOPICAL MICONAZOLE IS A POTENT INHIBITOR OF WARFARIN METABOLISM
Fluconazole (diflucan)- MOA
Azoles Triazoles
Inhibits synthesis of fungal membrane ergosterol
Lacks endocrine side effects
Penetrates CSF of normal and inflammed meninges
Fluconozole (diflucan)- uses, ROA and ADRs
DOC- cryptococcuss neoformans, candidemia and coccidioidomycosis, effective against all forms of mucocutaneous candidiasis; used prophylactically in immunocompromised pts
ROA- Oral or IV
ADRs- N/V and rash
Fluconazole (diflucan)- drug interactions
Moderate inhibitor of CYP3A4 (cyclosporin, lovastatin) and strong inhibitor of CYP2C9
Tetratogenic
Itraconazole (Sporanox)
Azoles triazoles
MOA- inhibits synthesis of fungal membrane ergosterol lacks endocrine side effects; -static
DOC- blastomycosis, aspergillis, sporotrichosis, paracoccidiodomycosis, histoplasmosis
Itraconazole (sporanoz)- pharmacokinetics and ADRs
PO- requires acid for dissolution
Extensively protein bound and distributes throughout most tissues including bone and adipose, but not CSF
Biologically an active metabolite
P450 INHIBITOR
Avoid in pregnancy
ADRs- N/V, rash, hypokalemia, HTN, edema, HA
Itraconazole (sporanox)- contraindications
Strong inhibitor and substrate of CYP34A, contraindicated w/ lovastatin, simvastatin, midazolam, triazolam. May decrease OCP effectiveness, and increased digoxin levels
Voriconazole (vfend)
Azole triazoles
PO or IV
Invasive aspergillosis and serious infections caused by scedosproium apiospermum and fusarium species
Penetrates tissues and CSF
ADRs- similar to other azoles; transient visual disturbance occurring shortly after dose
Voriconazole (vfend)- Contraindictations
Inhibitor of CYP2C18, 2C9, 3A4. Contraindicated in patients taking rifampin, phenobarital, carbamasepine. Dose adjustments may be required w/ statins, benzodiazepines, and warfarin
Posaconazole
Azole triazoles (new antigungal)
Only available as oral suspension and must be taken with high fat meal for adequate absorption
Spectrum similar to itraconazole, w/ additional effect on Zygomycetes such as mucor
More effective than other azoles in treating fungal infections in immunosuppressed patients (myelogenous leukemia, stem cell transplantation, refractory esophageal candidiasis)
Inhibits CYP3A4
Terbinafine (Lamisil)
Allylamines
MOA- prevents ergosterol synthesis by inhibiting the enzyme squalene oxidase; -cidal
PK- lipophillic- penetrates superficial tissues including the nails
Administered orally- fingernail and toenail regimens differ, 40% bioavailability due to 1st pass metabolism, therapy is 3 months.
Terbinafine (lamisil)- indications and ADRS
Active against dermatophytes and candida albicans
ADR- mild- HA, N/Dm rash, taste and visual disturbance
Rare but serious effects- cholestatic jaundice, blood dyscrasias, steven-johnson syndrome
Baseline LFTs and CBC (repeat q 4-6wks)
Onychomycosis (nail infection) treatments
Terbinafine- 1st line agent (not candida)
Itraconazole- alternative 1st line therapy (preferred for candida infections)
These drugs have REPLACED grseofulvin and ketoconazole for this type of infection
Caspofungin (Cancidas)
Echinocandins
2nd line therapy for those who failed amphoB or itraconazole (expensive)
Interferes w/ synthesis of fungal wall
Limited to aspergillus and candida species
ADRs- fever, rash, nausea, phlebitis, and flushing rxn.
Micafungin (Mycamine)
Echinocandins
Esophageal candidas
Prophylaxis of invasive candida infections in pts undergoing hematopietic stem cell transplantation
ADRs- fever, rash, nausea, phlebitis, and flushing rxn.
