DD 02-28-14 10-11am Antifungal Agents - French Flashcards
Amphotericin B (Fungizone) - Mechanism of Action
Binds to ergosterol in fungal cell membrane
- -> opens pores
- -> results in leakage of cellular constituents (Na+, K+, and H+ ions) *
- -> cell death (fungicidal)
-LESS selective toxicity b/c also binds cholesterol components in mammalian cells
Amphotericin B (Fungizone) - Pharmacokinetics
- Poor oral absorption (used IV or topically)
- Rapidly sequestered in tissues (liver, spleen, lymph nodes, lungs) - slowly released (little to CNS)
- Slowly excreted by kidney, major route through biliary tract (terminal t1/2 about 15 days)
- Also as bladder irrigation or intraventricularly / intracisternally / intralumbarly (fungal meningitis)
Amphotericin B (Fungizone) - Spectrum
Broad spectrum, in fungal infections including:
- opportunistic (Candida, Aspergillus)
- systemic (Histoplasma, Cryptococci, Blastomyces, Coccidioides)
Amphotericin B (Fungizone) - Clinical Uses
- Drug of choice for nearly all life-threatening systemic fungal infections (commonly in immunosuppressed pts such as cancer patient with neutropenia)
- Often used as initial induction therapy then replaced by newer, less toxic azoles
- Deep candidiasis, aspergillosis, mucormycosis, cryptococcosis, extracutaneous sporotrichosis
Amphotericin B (Fungizone) - Adverse Rxns
VERY TOXIC DRUG!!!
- Nephrotoxicity = major limiting factor
- Infusion-related toxicities: Chills, fever, vomiting, rigor, hypotension with IV use
- Anemia (75%) occurs secondary to bone marrow depression (via decreased erythropoeitin)
Nephrotoxicity w/ Amphotericin B
- Occurs in nearly all patients
- Attenuated somewhat w/ pretreatment saline infusion
Liposomal preps may reduce renal & infusion toxicities.
- Lipid vehicle serves as amphotericin reservoir reducing non-specific binding to human cell membranes (in theory)
- AmBisome, Abelcet
Infusion-related toxicities w/ Amphotericin B
- premedicate w/ acetaminophen/diphenhydramine or administer w/ hydrocortisone
- meperidine can shorten duration of rigors
Liposomal preps may reduce renal & infusion toxicities.
- Lipid vehicle serves as amphotericin reservoir reducing non-specific binding to human cell membranes (in theory)
- AmBisome, Abelcet
Nystatin (Mycostatin)
- Similar to Amphotericin B
- BUT toxicity limits use to topical treatment of Candidal infections of skin, mucous membranes, and GI tract
- Safe & effective for this indication
- No appreciable absorption from GI tract
- Toxicities limited to mild and transient GI upset
Echinocandins - examples
Caspofungin (Cancidas),
Anidulafungin (Eraxis),
Micafungin (Mycamine)
Echinocandins - Mechanism of Action
- Inhibits the synthesis of β (1,3)-D-glucan, an essential component of fungal cell walls
- -> leads to disruption of cell wall assembly
- High level of selective toxicity due to absence of these enzymes in mammalian cells
Echinocandins - Pharmacokinetics
- IV infusion
- Dosage reduction required for pts w/ hepatic insufficiency (NOT for anidulafungin)
- No dosage reduction required in renal dysfunction
- Dosage increase may be necessary if pt is also taking inducers of cytochrome P450 (phenytoin, rifampin, carbamazepine, certain HIV drugs)
Echinocandins - Spectrum / Clinical Uses
- Indicated for treatment of invasive aspergillosis in pts refractory / intolerant to other therapies (amphotericin B, itraconazole)
Echinocandins - Adverse Rxns
Histamine-mediated symptoms
- rash
- facial swelling
- pruritus
Other effects:
- fever
- n/v
- H/A
- phlebitis
Types of Azoles
Triazoles and Imidazoles
Triazoles - Examples
Fluconazole (Diflucan)
Itraconazole (Sporanox)
Voriconazole (Vfend)
Terconazole (Terazole) is topical only
Triazoles - Mechanism of Action
- Highly selective inhibition of fungal cytochrome P450 (14α-demethylase) reducing normal sterol synthesis
= FUNGISTATIC - Greater selectivity for fungal vs mammalian cytochrome enzymes than seen W/ imidazoles (ketoconazole)
- -> less hepatotoxicity, fewer hepatic enzyme interactions, & wider therapeutic index
Triazole Pharmacokinetics
- Oral bioavailability is 90-99%
- T1/2 of 30-40 hrs allows once daily dosing of each
Triazole Pharmacokinetics - Itraconazole
- absorbed best with food
- eliminated primarily by hepatic metabolism
Triazole Pharmacokinetics - Fluconazole
- cleared primarily by renal excretion of unchanged drug (80%) requiring dosage reduction in impaired renal function
- can enter CSF for treatment of meningitis
Triazole Clinical Uses - Fluconazole [& Itraconazole]
- Vaginal candidiasis in pts who fail treatment w/ topical agents
- Oropharyngeal & esophageal candidiasis
- also used in Itraconazole has potential benefit in treatment of aspergillosis, histoplasmosis, sporotrichosis
- Agent of choice in dermatophytoses & onychomycosis if systemic therapy chosen
Triazole Clinical Uses - Voriconazole
- new agent
- useful in serious invasive aspergillosis
- less toxicity than amphotericin
Triazoles - Adverse Effects
- Reported more frequently in HIV pts
- Overall very well tolerated
Most common: GI distress most common Also; - H/A - allergic rash - elevation of liver enzymes - transient visual changes (voriconazole)
- No inhibition of mammalian CYP450 steroid biosynthesis
Triazoles - Drug Interactions - Itraconazole & Fluconazole
- Interference w/ drug metabolism by itraconazole is similar to ketoconazole
- Inhibition by fluconazole somewhat less, but possible
Triazoles - Drug Interactions - Voriconazole
Voriconazole levels reduced by CYP450 inducers
Imidazoles - examples
Ketoconazole (Nizoral) - systemic (PO, IV) & topical use
Clotrimazole (Lotrimin / Mycelex) - topical only*
Miconazole (Monistat) - topical only*
- topical only due to extreme systemic toxicity
Imidazoles - Mechanism of Action
Inhibits P450-dependent enzyme (14α-demethylase)
- -> results in decreased levels of ergosterol
- -> Disruption in synthesis of cell membrane sterols leads to alterations in membrane permeability
- Fungistatic / Fungicidal depending on concentration
Imidazoles (Only Ketoconazole used systemically) - Pharmacokinetics
- Poorly absorbed, max absorption with low pH
- Well-distributed, but enters CNS poorly (5%)
- Crosses placenta & Excreted in breast milk
- Eliminated by hepatic metabolism (primarily by oxidation)
Imidazoles - Ketoconazole - Clinical Uses
- Decline in systemic use of ketoconazole due to availability of safer agents
- Chronic mucocutaneous candidiasis & other systemic fungal infections (ketoconazole, oral)
- less toxic than Amphotericin B but also less effective
- May antagonize amphotericin effect by preventing synthesis of ergosterol binding targets.
Imidazoles - topical Miconazole & Clotrimazole - Clinical Uses
- Oral & vaginal candidiasis (miconazole / clotrimazole, topically as creams and troches as high systemic toxicity occurs if these agents are given parenterally)
Imidazoles - Ketoconazole (systemic) - Adverse Rxns
*Side effect profile leading to decline in use
Most Common: Anorexia, n/v
- tolerance improves by taking w/ food or at bedtime
Pruritus, rash, and dizziness can occur
Hepatotoxicity (usually mild jaundice, can be serious/fatal rarely)
- generally avoid if preexisting liver dysfunction
Avoid in pregnancy (teratogenic in rat)
Can inhibit mammalian testosterone synthesis
- -> impotence, decreased libido, & gynecomastia
- due to greater propensity to inhibit mammalian CYP450 than triazole antifungal agents
High doses may also inhibit adrenal steroidogenesis & decrease plasma cortisol concentrations
Imidazoles - Ketoconazole - Drug Interaction
- Antacids / Cimetidine: Elevation of pH leads to decreased oral absorption
- Cyclosporine / Phenytoin / Anticoagulants: Ketoconazole is strong inhibitor of CYP3A4 drug metabolism leading to increased drug effect (or toxicity)
- Rifampin: Decreases effect of ketoconazole by inducing metabolism
Terbinafine (Lamisil)
Synthetic allylamine antifungal
Terbinafine (Lamisil) - Mechanism of action
- Interferes w/ ergosterol synthesis by inhibiting squalene oxidase
- Toxic effects also from accumulation of squalene
- Fungicidal
- Accumulates in keratin (like griseofulvin)
Terbinafine (Lamisil) - Pharmacokinetics / Clinical Uses
- Agent of choice in once daily oral dose for toe / finger nail infections (onychomycosis)
- Topical for athlete’s foot (tinea cruris, tinea corporis)
Terbinafine (Lamisil) - Adverse effects
- GI upset, rash, headache, taste disturbances
- Interference with CYP450 metabolism
Flucytosine (Ancobon) - Mechanism of action
- Converted in fungal cell into 5-fluorouracil (via cytosine deaminase)
- -> interferes w/ DNA synthesis
- -> leads to cell death
-High selective toxicity (mammalian cells lack deaminase)
Flucytosine (Ancobon) - Resistance
- Resistance in fungi that lack cytosine deaminase
Flucytosine (Ancobon) - Pharmacokinetics
- Well absorbed after oral administration
- Given in 4 equally spaced doses
- Excellent distribution to tissues (including CNS)
- 90% excreted unchanged in urine
- Requires decreased dosage if diminished renal function
Flucytosine (Ancobon) - Spectrum / Clinical Uses
Effective agent, but rarely given alone
- given w/ Amphotericin B due to resistance development
Used for serious infections of cryptococcosis, candidiasis, and chromoblastomycosis
Flucytosine (Ancobon) - Adverse Rxns
Nausea, vomiting, skin rashes occasionally
Prolonged high levels --> bone marrow depression --> abnormal liver function --> hair loss. Probably due to bacterial conversion of flucytosine to 5-FU in intestine
Griseofulvin (Fulvicin) - Mechanism of action
- Binds to microtubules inhibiting fungal mitosis & interfering w/ processing of new cell wall components
- FUNGISTATIC
Griseofulvin (Fulvicin) - Pharmacokinetics
Poor oral absorption generally
- can be improved by reducing particle size (microsize/ultramicrosize)
- can be improved by administration with fatty foods
-Topical use has little effect
- Little griseofulvin present in body fluids or tissues
- Excreted chiefly in feces
Griseofulvin (Fulvicin) - affects of skin
Absorbed drug has affinity for diseased skin
- binds to keratin
- -> makes it resistant to fungal growth
- as keratinized structures shed, tend to be replaced by uninfected ones
Griseofulvin (Fulvicin) - Clinical uses
Indicated for severe dermatophytosis (superficial) involving:
- skin and hair (3-6 weeks)
- fingernails (3-6 months)
- toenails (6-12 months)
*Infrequently used, replaced by shorter course of therapy with itraconazole or terbinafine (3 months)
Griseofulvin (Fulvicin) - Adverse effects
- Hypersensitivity rxns most common (skin rashes, urticaria, angioneurotic edema)
- Occasionally headache (can be severe), GI distress, mental confusion
Pentamidine (Pentam) - Mechanism of Action
Inhibits protein and nucleic acid synthesis
Pentamidine (Pentam) - Pharmacokinetics
- Usually given IV/IM
- inhalation can produce higher levels & lower toxicity in treating P. jirovici (carinii) pneumonia (common opportunistic fungal infection in AIDS patients)
Pentamidine (Pentam) - Clinical Uses
- Effective against wide variety of protozoa (concentrated in organisms)
- Agent of choice in treatment of P. jirovici (carinii) pneumonia in AIDS patients (or trimethoprim / sulfamethoxazole [Bactrim])
- Bactrim preferred for treatment in non-AIDS patients & for prophylaxis in all patients
Pentamidine (Pentam) - Adverse Reactions
- Severe toxicities often limit use w/ 50% of patients receiving pentamidine show some adverse effect
- Leukopenia, hypoglycemia, hypotension (IV use)
- Nephrotoxicity / hepatotoxicity more common, less severe
Background on Fungal Infections
- Uncommon in healthy, immunocompetent individuals w/ exception of mucosal candidiasis & dermatophyte skin infections (e.g., athlete’s foot)
- Affect 10-20% of population at any given time
- Account for > 2 million office visits a year
Superficial fungal infections - examples
[pityriasis versicolor, tinea nigra, black piedra, white piedra]
Superficial fungal infections - overview
- Limited to outermost layers of the skin & hair that do not elicit a cellular response from the host
- Usually produce only cosmetic problems that are easily diagnosed & treated.
Superficial fungal infections - treatment
- Removal from the skin w/ keratolytic agents (selenium, salicylic acid)
AND / OR
- Topical azole-antifungal agents
- ketoconazole (cream-shampoo-gel-foam)
- miconazole
- clotrimazole
Cutaneous-Mucocutaneous Fungal Infections - 2 types
Dermatophytes
Candida (esp. albicans)
Dermatophytes (Cutaneous-Mucocutaneous Fungal Infections) - examples
Microsporum Tricophyton Epidermophyton, e.g. ... - tinea corporis (ringworm) - tinea pedis (Athlete’s Foot) - tinea cruris (Jock Itch) - tinea capitis (scalp) - tricophyton rubrum (nails)
Dermatophytes (Cutaneous-Mucocutaneous Fungal Infections) - overview
- Includes infections that are deeper in the epidermis & its integuments, the hair and nails
- Generally restricted to keratinized layers of integument & its appendages
- Clinical manifestations of these infections are referred to as ringworm or tinea
Dermatophytes (Cutaneous-Mucocutaneous Fungal Infections) - treatment
- Generally conservative w/ use of topical antifungal agents (clotrimazole, miconazole, butenafine, terbinafine)
Hair infections: griseofulvin PO
Nail infections (onychomychosis)
- Generally requires systemic therapy of 6 wks - 6 mos duration (itraconazole, terbinafine)
- Topical therapy (ciclopirox) is of low efficacy
- Fingernail infections will usually always clear
- Toenail infections respond in ~60-70 % of cases
Candida (Cutaneous-Mucocutaneous Fungal Infections) - overview
- esp. albicans
- Part of normal human flora
- Includes disease that affect mucosal surfaces of mouth, vagina, esophagus, & bronchial tree
- Also diseases of skin & nails that mimic dermatophyte infections
Candida (Cutaneous-Mucocutaneous Fungal Infections) - treatment
- Topical nystatin, clotrimazole, butoconazole, terconazole for mucocandidiasis
- Can try fluconazole via systemic (oral) route if no response
Subcutaneous Fungal Infections - examples
Sporotrichosis
Chromoblastomycosis
*relatively rare
Subcutaneous Fungal Infections - Overview
- Infections that involve the dermis, subcutaneous tissues, muscle, & fascia
- Characterized by development of lesions on skin surface
- Usually sites of trauma where organism is implanted in tissue
Subcutaneous Fungal Infections - Treatment
- Oral itraconazole
- Parenteral amphotericin B (severe systemic infection)
Systemic Fungal Infections - Examples
Blastomycosis
Coccidioidomycosis
Cryptococcosis
Histoplasmosis
Systemic Fungal Infections - Overview
- Infections that originate primarily in lung but may spread to many organ systems
- Causative organisms are inherently virulent & cause disease in healthy humans
- Respiratory infections are generally asymptomatic
- Secondary spread to other organs causes pt to seek medical attention
- Host’s immune status determines severity of disease, which can be life-threatening in immunocompromised patients if therapy not rapid
Systemic Fungal Infections - Treatment
- Long term therapy w/ systemic amphotericin B infusions generally required
Systemic Fungal Infections - Treatment of Blastomycosis
amphotericin B > itraconazole > voriconazole > fluconazole > ketoconazole
Systemic Fungal Infections - Treatment of Coccidiodomycosis
- amphotericin B
- maintenance w/ fluconazole or itraconazole
Systemic Fungal Infections - Treatment Cryptococcosis
amphotericin B ± flucytosine, fluconazole
Systemic Fungal Infections - Treatment of Histoplasmosis
amphotericin B
itraconazole
Opportunistic Fungal Infections - Examples
Candida albicans
Aspergillus fumigatus
Pneumocystis carinii
Opportunistic Fungal Infections - overview
- Host debilitation increases susceptibility to fungal infections
- Becoming more common & medically significant due to AIDS and increased use of radiation & cytotoxic drug therapy in cancer & transplant patients
Opportunistic Fungal Infections - Treatment of Candidiasis (disseminated)
fluconazole
micafungin-caspofungin
posaconazole
Opportunistic Fungal Infections - Treatment of Aspergillosis
amphotericin B
caspofungin
voriconazole
itraconazole
Opportunistic Fungal Infections - Treatment of Pneumocystis pneumonia
TMP-SMX
pentamidine
