Flashcards in Antifungal drugs Deck (50):
Amphotericin B, a polyenes used to treat systemic antifungal infections, what makes it so good and what makes it so bad?
good: broadest spectrum
bad: significant adverse side effects
(there are newer liposomal formulations associated with increased efficacy and decreased toxicity)
How is amphotericin given, what is its mechanism of action?
1. binds to ergosterol in fungal membrane
2. forms pore in the membrane thereby increasing membrane permeability
3. efflux of essential molecules
4. fungal death
-binds only weakly to cholesterol
What is amphotericin B not active against?
1. Candida Lusitaniae
2. Pseudallescheria boydii (scedosporium apiospermum)
When is amphotericin used?
initial induction therapy (usually 4 weeks) to reduce fungal burden, then replaced by newer less toxic AZOLE drugs for consolidation therapy and prevention of relapse
What is the ONLY antifungal agent that is approved in pregnant/ breast feeding women?
What is amphotericin the treatment of choice for?
What are the adverse infusion related effects for amphotericin a drug with a low therapeutic index ?
1. infusion related
-fever, chills, muscle spasms, vomiting, headache and hypotension
a. slow rate/decrease dose
b.preemptive meds like antipyretic,antihistamine, corticosteroids
What are the cumulative toxicities of amphotericin B?
a. reversible-decreased renal perfusion via vasoconstriction
-reduce by using saline drip (Na loading)
b. non reversible
-renal tubular injury(prolonged administration)
-tubular acidosis and severe K+ and Mg2+ wasting
-more common in presence of diuretics or other nephrotoxic meds eg. aminoglycosides/cyclosporine
2. hepatotoxicity (occasional)
-reversible suppression of erythrocyte production due to decreased EPO
What are the bad parts of flucytosine and the good part?
1. narrow spectrum of activity
2. use is restricted by high incidence of resistance
-mutations in cytosine permease, cytosine deaminase, uracil phosphoribosyl transferase or increase in cytosine synthesis
good penetration into the CSF
-used for cryptococcal meningitis
Is flucytosine used alone?
no typically in combination with other antifungal drugs
-especially ampho B and an azole
-ampho enhances flucytosine permeability
How is flucytosine eliminated?
renally-dosage adjustment required in presence of renal insufficiency
What is the mechanism of action of flucytosine?
1. taken up via cytosine permease
2. fungal specific cytosine deaminase -->5 fluorouracil
2. inhibits both DNA(thymidylate synthase) and RNA synthesis
What does flucytosine+amphotericin B treat?
cryptococcosis and candidiasis
-cryptococcal meningitis (good CSF penetration of flucytosine and ampho b enhances fungal uptake of flucytosine)
What does flucytosine + itraconazole treat?
What are the adverse effects of flucytosine?
1. endogenous gut microflora express cytosine deaminase -->5 fluorouracil (antimetabolite)-->toxicity
-GI: nausea, vomiting diarrhea
-Bone marrow toxicity: anemia, leukopenia, thrombocytopenia
What is the prototype imidazole?
What is the order of spectrum of activity for the triazoles?
What is the mechanism of action of azoles?
Azoles are fungistatic/fungicidal
1. Inhibit 14 alpha demethylase (CYP45) involved in biosynthesis of ergosterol from lanosterol
-impairs membrane function
-increases membrane permeability
-decreases activity of membrane associated proteins
What are the common adverse side effects of all azoles?
1. GI distress
2. Hepatotoxicity-requires hepatic enzyme monitoring
3. fetal abnormalities
When should itraconazole and voriconazole never be given to a patient?
when the patient is taking statins due to increased risk of developing rhabdomyolysis
What azoles have good CNS penetration?
fluconazole and voriconazole
What azole needs real adjustment?
What limits ketoconazole use?
-oral ketoconazole requires acidic environment for absorption
-poor penetration into CSF and urine
-many adverse effects due to inhibition of CYP450 enzymes involved in adrenal and gonadal steroid synthesis
-->decreased cortisol and decreased testosterone
--->gynecomastia, libido, impotence, menstrual irregularities, hypotension and fatigue
-many drug interactions of CYP450 3A4
-rarely used now, largely replaced by itraconazole
-still used topically to treat dermatophyte infections
What is the spectrum of activity fluconazole?
Narrowest spectrum of activity of all azole drugs but
-good oral bioavailability and EXCELLENT penetration into the CSF
-fewest drug interactions of all azoles
Does fluconazole have many adverse effects?
no only minor effects: nausea, headache, skin rash and GI, and alopecia (reversible, long/high dose)
How is fluconazole eliminated?
80% of drug eliminated unchanged in the urine
-useful in treatment of fungal BLADDER infections
What does fluconazole used to treat?
-poor activity toward C. glabrata and no activity against C. krusei
2. TREATMENT OF CHOICE
for cryptococcal meningitis
-used as consolidation/maintenance therapy with ampho b/flucytosine
3. good activity against coccidioides
4. variable activity against endemic dimorphic fungi
-less active than itraconazole against histoplasmosis, balstoplsmisis, sporotrichosis
-only used if itraconazole not well tolerated
What is fluconazole the therapy of choice for?
1. Cryptococcal meningitis
2. coccidioidal meningitis
What should itraconazole not be used for?
HOw is the spectrum of activity of itraconazole vs. fluconazole?
broader spectrum but more adverse effects and many potential drug interactions
What are the clinical uses of itraconazole?
1. oral treatment of dermatophytes
2.oral treatment of onychomycosis
3. preferred agent for non-meningeal blastomyces/histoplasma/coccidioides
4. effective against candida
-but more adverse effects than fluconazole
5. active against aspergillus
-less effective than voriconazole
What are the adverse effects of itraconazole?
3. Peripheral edema
Can cause CHF in patients with ventricular dysfunction
-not be used if history of ventricular dysfunction or CHF
What is the spectrum of voriconazole?
newer extended spectrum azole
-distributed into CSF (absorption inhibited by fatty meals, bioavailability is unpredictable and affected by genetic polymorphisms)
-less toxic than ampho b but has unique side effects
-non linear dosing
-inhibitor of CYP2C19, 2c9, 3a4
What is the spectrum of activity for voriconazole?
1. Excellent activity against candida
-even C. Glabrata and C. krusei
2. good activity against dimorphic fungal infections
-blastomycosis, histoplasmosis, sporothrix, coccidioidomycosis
3. effective against pseudoallerischerideri boydii/scedosporium
4. enhanced activity against aspergillus and fusarium
-treatment choice for aspergillus
What is voriconazole the drug of choice for?
What the side effects to voriconazole?
1. periostitis (bone pain-associated with long term therapy)
-inflammation of the periosteum
2. transient vision changes-visual blurring
-flashes of light
-changes in color vision
--affects 30% of patients
--seen after first dose/diminishes with time
3. photosensitivity/rash-rarely Stevens Johnson syndrome
associated with high concentrations >5.5
4. visual/auditory hallucinations
Posaconazole is the newest azole what is its spectrum of azole family?
-maybe poor penetration to CSF and urine
What is posaconazole used for?
1. treatment of invasive fungal infections
-candida and aspergillus
2. antifungal prophylaxis in neutropenia
3. salvage therapy for mucormycosis
******only azole effective against zygomycosis/mucormycosis
How do echinocandins work?
-competitively inhibit B 9(1-3) D glucan synthase complex involved in biosynthesis of the principal building block of the fungal wall
-impairs structural integrity of fungal wall
-increases osmotic instability leading to cell wall death
Does echinocandins penetrate the CSF do they inhibit CYP450?
What is the spectrum of activity for echinocandins?
1. Candida (including glabrata and krusei)
-fungicidal with minimal effects
-used in salvage therapy for invasive aspergillosis that fail initial treatment with ampho b or voriconazole
-NO Significant activity toward cryptococcus or dimorphic fungi
What are systemic antifungal drugs for cutaneous infections?
griseofulvin and terbinafine
What does grisoefulvin treat?
mycotic infections of skin, nail, and hair due to:
no activity against any other fungi
What are the side effects of griseofulvin?
1. nervous system; headache, lethargy, vertigo and blurred vision
2. skin: urticaria, photosensitivity, rash and skin eruptions
3. hepatotoxicity (rare)
4. leukopenia, neutropenia and monocytosis (rare)
5. fetal abnormalities
-inducer of CYP450
What is the mechanism of action of griseofulvin? IS it static or cidal
-binds to fungal microtubules preventing the formation of mitotic spindles inhibiting fungal mitosis
-treatment needs to be continued until affected tissue is completely replaced by new tissue
Terbinafine an oral antifungal agent deposits where? What is its activity and clinical use?
deposits in the skin, nail hair and fat
-activity is limited to dermatophytes and candida albicans
-cure rate is 90% effective-MORE effective than griseofulvin or itraconazole!
What is the mechanism of action of terbinafine?
inhibition of fungal squalene epoxidase
1. increased squalene-->toxic products
2. impaired fungal membrane function
What is nystatin? What is its MOA? What does it treat?
-similar to Amho B-binds to ergosterol and forms pores in the fungal membrane
--to toxic for IV administration
-not significantly absorbed from sin, mucus membrane or GI tract
*NOT active against dermatophytes
-used in the treatment of oral candidiasis (swish and swallow)
What are the topical azoles?
clotrimazole, miconazole, terconazole
creams, lozenges, suppositories
1. oral and vulvovaginal candidiasis
2. dermatophyte infections