Term
| Whats the line up like for this section? |
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Definition
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Term
| What are the 2 main grps for the superficial mycoses? |
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Definition
| Dermatophytoses & candidiasis |
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Term
| What fungal infections do HIV pts suffer from? |
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Definition
| Crytococcal meningitis & aspergillosis |
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Term
| What is the 4th MCC of septicemia? |
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Definition
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Term
| What revolutionalized fungal Tx? |
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Definition
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Term
| How are anti-fungal Rxs classified by MOA? |
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Definition
1. DRUGS THAT ALTER CELL MEMBRANE PERMEABILITY:
•Polyenes: Amphotericin B & Nystatin.
•Azoles: Ketoconazole, Fluconazole, Itraconazole, Voriconazole, Posaconazole, Clotrimazole, Miconazole.
•Allylamines: Terbinafine
2. DRUGS THAT BLOCK NUCLEIC ACID SYNTHESIS (ANTIMETABOLITES): Flucytosine.
3. DRUGS THAT DISRUPT MICROTUBULE FUNCTION: Griseofulvin.
4. DRUGS THAT DISRUPT THE FUNGAL CELL WALL: Echinocandins - Caspofungin. |
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Term
| How are anti-fungal Rxs classified by clinical use? |
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Definition
1. SYSTEMIC DRUGS FOR SUBCUTANEOUS & SYSTEMIC MYCOSES: •Polyenes - Amphotericin B. •Flucytosine. •Azoles: Ketoconazole, Fluconazole, Itraconazole, Voriconazole, Posaconazole. •Echinocandins - Caspofungin. 2. DRUGS FOR SUPERFICIAL MYCOSES:
A. SYSTEMIC DRUGS FOR SUPERFICIAL MYCOSES •Griseofulvin. •Allylamines - Terbinafine. •Azoles - Ketoconazole, Fluconazole, Itraconazole.
B. TOPICAL DRUGS FOR SUPERFICIAL MYCOSES •Polyenes - Amphotericin B & Nystatin. •Azoles - Clotrimazole, Miconazole, Ketoconazole. •Allylamines - Terbinafine |
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Term
| What is the first choice for systemic mycoses? |
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Definition
Amphotericin B, its a polyene macrolide produced by streptomyces nodosus. Sometimes used in combo w/ flucytosine.
MOA - binds to ergosterols and forms pores, thus lil resistance.
PK - highly insol thus dissolved w/ deoxycholate colloidal suspension and given IV as poor GI absorption and lil cross to CSF this given intrathecally for serious meningeal Dz. In the blood 90% of Rx binds rapidly to tissue and the rest bind to plasma protein. NB however that it can cross placenta. Found in bile and urine.
Uses - against Aspergillus, Candida albicans, Cryptococcus, Histoplasma, and Mucor. But has a low therapeutic index thus given by slow IV. |
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Term
| What are the two kinds of A/Es of Amphotericin B use? |
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Definition
A) Infusion-related:
Nearly universal. Fever and chills, muscle spasms, vomiting, headache and
hypotension. They can be attenuated by slowing infusion rate or decreasing daily dose. Pre-medication with antihistamines, glucocorticoids, antipyretics or meperidine can be helpful. Small test doses (1mg) are administered to assess negative response.
B) Slower toxicity:
In all pts, the decreased GFR is reversible but the tubular injury is irreversible and is usually the result of tubular acidosis w/ severe Mg2+ & K+ wasting and attenuated w/ sodium loading. Reduced EPO -> hypochromic normocytic anemia (???). Less dose can be used when given w/ flucytosine. NB that intrathecal admin can cause seizures & serious neurological damage |
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Term
| What can be done to reduce the nephrotoxicity w/ Amphotericin? |
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Definition
| Lipid formulations for IV to prevent high Rx exposure to PCT. NB however that liver toxicity which is not there with amphotericin B deoxycholate but is present w/ these lipid formulations |
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Term
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Definition
| Synthetic pyrimidine antimetabolite. Used only in combo w/ amphotericin to Tx systemic mycoses & meningitis caused by Crytococcus neoformans (+ amphotericin B) & Candida, and (dermatiaaceous moldi that cause chromoblastomycosis (+ itraconazole)) |
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Term
| What is the MOA and PK of Flucytosine? |
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Definition
| Taken up by the enzyme cytosine permease, then converted to 5-fluorouracil (5-FU) then to 5-fluorodeoxyuridine monophosphate (5-FdUMP), which inhibits thymidylate synthetase thus no dTMP. Formed 5-FUTP inhibits protein synthesis (?). NB that mammalian cells can convert parent Rx. Also not that combo of Flucytosine & Amphotericin B is synergistic |
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Term
| What are the A/Es of Flucytosine? |
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Definition
| Besides fungi, intestinal flora take these up and convert it to the antineoplastic compound 5-FU -> BM toxicity w/ anemia, leukopenia, thrombocytopenia are most common; less frequent is LFT elevation; toxic enterocolitis can occur |
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Term
| How are the Azoles grped? |
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Definition
A) IMIDAZOLES
• Ketoconazole
• Miconazole
• Clotrimazole
B) TRIAZOLES
• Itraconazole
• Fluconazole
• Voriconazole
• Posaconazole |
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Term
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Definition
Safer, oral, synthetic, first came the Imidazoles followed by the Triazoles which are more specific.
MOA - The fungus-specific cytochrome P450 enzyme 14α-sterol demethylase catalyzes the conversion of lanosterol to ergosterol. Azole antifungal drugs inhibit 14α-sterol demethylase, thus reducing ergosterol synthesis. |
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Term
| What are some of the A/Es of the azoles? |
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Definition
• Relatively nontoxic. Most common adverse reaction: minor gastrointestinal upset.
• May cause abnormalities in liver enzymes.
• Very rarely: clinical hepatitis. |
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Term
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Definition
1st oral azole now seldom used. The other azoles have fewer A/Es. Greater propensity than fluconazole & itraconazole to inhibit mammalian P450 enzymes. Ketoconazole can decrease plasma testosterone & cause gynecomastia, decreased libido and loss of potency & menstrual irregularities. High doses inhibit adrenal steroid synthesis & decrease plasma cortisol conc.
• Strong inhibitor of CYP3A4, thus potentiate the toxicities of warfarin and cyclosporine. Best absorbed at low gastric pH, thus no Antacids, H2 blockers or PPIs. Poor penetration in the CSF.
A/Es: GI (high doses), Hepatic toxicity, including fatal hepatic necrosis, can occur. Uses: Due to its narrow spec & A/Es no systemic use. Instead used for chronic mucocutaneous candidiasis and is also effective against dermatophytes. |
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Term
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Definition
Good CSF penetration. Unlike ketoconazole and itraconazole, its oral bioavail is high. Oral & IV. Moderate inhibitor of CYP3A4. Strong inhibitor of CYP2C9: can increase plasma levels of phenytoin, zidovudine and warfarin. Renal 90% excretion.
DOC in esophageal, oropharyngeal and vulvovaginal candidiasis. DOC for most infections due to Coccidioides. DOC for initial and secondary prophylaxis against criptoccocal meningitis. AIDS pts successfully treated for criptoccocal meningitis need lifelong suppressive therapy w/ fluconazole.
Indicated for treatment of criptoccocal meningitis in those with normal mental status and CSF cryptococcal antigen titer <1: 1024. IV fluconazole is equivalent to amphotericin B in treatment of candidemia in ICU patients with normal WBC counts. Prophylactic use of fluconazole reduces fungal disease in bone marrow transplant recipients and AIDS patients, but the emergence of fluconazole-resistant fungi has raised concerns about this indication. Fluconazole is ineffective against Aspergillus or other filamentous fungi. |
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Term
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Definition
Oral. Metabolized in the liver, primarily by the CYP3A4. Its metabolism may be affected by both inducers and by inhibitors of the enzyme. Strong inhibitor of CYP3A4. May cause fatal arrhythmias when given concurrently with cisapride or quinidine. Its effects on metabolism of other hepatically cleared drugs are much less than those of ketoconazole. Doesn’t affect mammalian steroid synthesis. Potent antifungal; poor bioavail. Penetrates poorly in CSF. Needs low pH for absorption
Preferred azole for mycoses due to the dimorphic fungi Blastomyces, Sporothrix
and Histoplasma. Effective against Aspergillus, but has been replaced by voriconazole for this indication. Used extensively for dermatophytoses & onychomycosis. Not active against Zygomycetes. |
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Term
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Definition
IV & oral (well absorbed). Bioavail over 90%. Spectrum similar to itraconazole. But more effective against Aspergillus and some species of Candida (including fuconazole-resistant species such as Candida krusei). Unlike itraconazole, it is active against Fusarium. Not active against zygomycetes. Replaced amphotericin B for TX of invasive aspergillosis.
Toxicities include rash, elevated liver enzymes and transient visual disturbances. Transient visual disturbances occur in up to 30% of patients, and include blurring and changes in color vision or brightness.
Voriconazole is metabolized by and inhibits CYP2C19, CYP2C9 and CYP3A4. Limiting its use. |
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Term
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Definition
• Posaconazole has an antifungal spectrum similar to that of itraconazole, but unlike other
azoles it has activity against Zygomycetes such as Mucor. Before approval of posaconazole, amphotericin B was the only agent available for treatment of Zygomycete infections.
• Only available as an oral suspension and must be taken with high-fat meals for adequate absorption.
• Inhibits CYP3A4. |
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Term
| Echinocandins: Caspofungin |
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Definition
| Newest class, Large cyclic peptides linked to a long-chain fatty acid. Active against candida and aspergillus but not Cryptococcus neoformans. Only IV. Inhibit synthesis of β(1-3)-D-glucans in the fungal cell wall. This results in disruption of the fungal cell wall and cell death. Extremely well tolerated. Minor gastrointestinal side effects and flushing. Elevated liver enzymes have been observed when caspofungin was co-administered with cyclosporine; this combination should be avoided. Uses: Disseminated and mucocutaneous candida infections and for empiric antifungal therapy during febrile neutropenia. Also in Invasive aspergillosis that has failed to respond to amphotericin B. |
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Term
| What are the superficial skin infections called? |
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Definition
Dermatophytes. Common
dermatomycoses such as tinea infections are often referred to as ringworm. |
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Term
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Definition
FungiSTATIC drug. Only used to TX dermatophytosis. Absorption improved with fatty foods. Enters susceptible fungal cells by energy-dependent process. Interacts with microtubules of the fungus to disrupt mitotic spindle and inhibit mitosis. It accumulates in the infected, newly synthesized, keratin-containing tissues, making them unsuitable for the growth of the fungi. It must be administered for 2-6 weeks for skin and hair infections. Nail infections require therapy for months but relapse. Indicated for severe dermatophytoses of the skin, hair, and nails. Largely replaced by newer antifungal drugs like itraconazole and terbinafine.
Allergy, headaches, mental confusion, GI irritation, photosensitivity, changes in liver function as seen. Induces liver P450 enzymes, thus increasing the metabolism of warfarin, etc. |
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Term
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Definition
Synthetic allylamine oral. In the ergosterol synthesis pathway, squalene is converted to lanosterol by the axn of the fungal enzyme squalene epoxidase. Terbinafine inhibits squalene epoxidase, thus preventing formation of lanosterol, which is a precursor of ergosterol. It also causes accumulation of toxic levels of squalene in the fungal cell, making it fungicidal. Like griseofulvin it accumulates in keratin but is much more effective in onychomycosis.
A/Es: GI upsets, rash, headache, taste disturbances. Terbinafine doesn’t affect the P450 system and has no significant drug interactions. |
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Term
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Definition
• Ketoconazole, fluconazole and itraconazole are commonly used orally for the treatment of dermatophytoses.
• Pulse or intermittent dosing with itraconazole is as effective in onychomycoses as continuous dosing because the drug persists in the nails for several months. Advantages
of pulse dosing include lower incidence of side effects and lower costs. |
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Term
| What abt topical Rxs for superficial infections? |
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Definition
• Topical treatment is useful in many superficial fungal infections, ie, those confined to the stratum corneum, squamous mucosa, or cornea. Such diseases include dermatophytosis (ringworm), candidiasis, tinea versicolor, piedra, tinea nigra, and
fungal keratitis.
• Topical administration is usually not successful for mycoses of the nails
(onychomycosis) and hair (tinea capitis) and has no place in the treatment of
subcutaneous mycoses such as sporotrichosis and chromoblastomycosis. |
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Term
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Definition
Polyene macrolide that is structurally similar to amphotericin B and has the same MOA. Too toxic for IVm thus oral.
Used only for candidiasis. Nystatin is not absorbed from the GI tract, skin, or vagina. Topical preparations include ointments, creams, and powders. Infections of the nails and hyperkeratinized or crusted skin lesions do not respond. Nystatin suspension is usually effective for oral candidiasis.
A/Es: bitter taste & occasional nausea.
Troches are available for the TX of oral candidiasis, and oral tablets for the TX of non-esophageal membrane GI candidiasis. |
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Term
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Definition
Topical amphotericin B is used for cutaneous candidiasis. A lotion, cream and ointment are
marketed. These preparations contain 3% amphotericin B. |
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Term
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Definition
• The topical azoles have a wide range of activity against dermatophytes and yeasts, including Candida albicans and Pityrosporum orbiculare.
• The two azoles most commonly used topically are clotrimazole and miconazole. Both available over-the-counter. Often used for vulvovaginal candidiasis. Absorption is negligible and adverse effects are rare.
• Topical and shampoo forms of ketoconazole are also available. |
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Term
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Definition
| Available as topical cream. Effective for tinea cruris and tinea corporis. Acts by inhibiting squalene epoxidase. |
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