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10-27-b: Antifungal agents: Targets
- Cell wall: Marinoptorein, beta glucan, chitin, mannoprotein
- Cell membrane: ergosterol* - azoles inhibit synthesis of ergosterol
- Cytoplasm: protein synthesis
- Nucleus: DNA
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Amphotericin B
- Very broad spectrum of activity
- Binds to the primary fungal cell membrane sterol – ergosterol
- Binding disrupts osmotic integrity of fungal membrane
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Lipid formulations of amphotericin B
- Better distribution, so have reduced infusional and renal toxicity
- Efficacy of lipid formulation is at least similar to conventional amphotericin B
- BUT: expensive
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AZOLES
- Sterol 14 alpha-demethylase is the single cytochrome P450 required for sterol byosynthesis in different phyla
- It is the most widely distributed P450 gene family being found in all biological kingdoms
- In fungi, this enzyme conferts lanosterol to ergosterol, the key constituent of the cell membrane
- All azoles act by inhibition of this enzyme
- Cross inhibition of mammalian CYP 450 isoenzymes, leading to reduced clearance of drugs metabolized by the liver through these pathways!!:
- Be aware of potential drug-drug interactions and need to modify drug dowing:
- Cholestasis observed with all azoles
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Drug-drug interactions with azoles
- Azoles increase the blood levels of many drugs metabolized through this pathways:
- Cyclophosphamide, warfarin, astemizole, terfenidine, protease inhibitors, vinca alkaloids, benzodiazepines, calcium channel blockers, statin drugs, cisapride, cyclosporine, tacrolimus, sirolimus, methylprednisolone, digoxin, quinidine
- Itraconazole and voriconazole are themselves metabolized by cytochrome p450 isoenzymes:
- Certain drugs increase the metabolism of itraconaole and voriconazole beause they prime the hepatic cytochrome P-450 system (rifampin, phenytoin)
- Drug-drug interactions are manageable by being aware of them, making dose adjustments, and monitoring drug levels:
- Fluconazole: mainly renal clearance
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Fluconazole
- IV and oral:
- Oral bioavailability > 90%:
- 19-hour half-life:
- Mostly renally cleared: dose reduction required with significant renal damage
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Fluconazole: uses
- Candidiasis: blood stream, oral “thrush”, systemic infections cause by Candida sp. , vaginal candidiasis – single 150 mg dose
- Cryptococcal meningitis:
- Dimorphic fungi (e.g. coccidioidomycosis):
- Prophylaxis in patients at high risk for fungal infection:
- Active against yeasts, not molds:
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Candida species
- Candida albicans: ~50% of Candida blood stream isolates
- Non-albicans Candida species:
- Candida parapsilosis: almost always catheter-related, better prognosis
- Candida glabrata: broad range of MICs to fluconazole
- Candida krusei: always fluconazole-resistant
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Fluconazole-resistant Candida species:
- Increased production of target enzyme: sometimes overcome by increasing fluconazole dosage
- Increased efflux of drug:
- Mutation of target enzyme: probably most common
- Candida species that are resistant to fluconazole are commonly cross-resistant to broader spectrum azoles, including itraconazole, voriconazole and posaconazole
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Ketoconazole
- Most common use probably topical
- Oral tablet, cream, and dandruff shampoo formulations
- Second-line drug as a systemic agent due to safer agents, itraconazole and fluconazole
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Ketoconazole side-effects
- Liver enzyme abnormalities
- Anti-thyroid function by impairing thyroglobulin iodination
- May decrease testosterone and cortisol levels, resulting in gynecomastia and oligospermia in men and menstrual irregularities in women: can be exploited therapeutically, e.g. to suppress androgen production in prostrate cancer
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Azoles active against aspergillus and other molds
- Itraconazole:
- Voriconazole:
- Posaconazole:
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Itraconazole
- Unpredictable oral bioavailability: monitor serum levels
- Reduces cardiac systolic function: contraindicated in patients with reduced ejection fraction or prior history of heart failure
- Edema:
- Hypokalemia:
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Voriconazole: toxicity
- Potential for drug-drug interactions: most common
- Liver enzyme abnormalities: second most important
- Visual:
- Potential for nephrotoxicity with IV administration of cyclodextrin vehicle in patients with pre-existing renal impairment:
- Skin changes (long-term use):
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Posaconazole
- Broad-spectrum azole, active against the major pathogenic yeasts and molds, including zygomycetes
- Currently, only available as an oral formulation
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Posaconazole prophylaxis in high-risk patients
- Neutropenia: prophylaxis with posaconazole led to
- Fewer invasive fungal infections (IFI) and less orverall mortality compated to fluconazole or itraconazole in neutropenic patients with ACUTE LEUKEMIA or MYELODYSPLASTIC SYNDROME
- Graft-versus-host disease (GVHD)
- Prophylaxis with posaconazole led to a reduction in the incidence of IA, in the total number of IFIs while on treatment, and in the number of deaths attributed to fungal infection
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Terbinafine (lamisil)
- Inhibits squalene epoxidase, an enzyme infolved in ergosterol synthesis:
- Oral and topical formulation:
- Mainly used for treatment of dermatophyte infection, including onychomycosis:
- Side effects: Generally well-tolerated:
- Liver toxicity is uncommon, but can be serious or fatal (FDA warning)
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Flucytosine
- Inhibits fungal protein synthesis by replacing uracil with 5-fluorouracil in fungal RNA:
- Also interferes with fungal DNA synthesis:
- Major use is in combination with amphotericin B for cryptococcal meningitis: modest benefit in clearance of infection compared to amphotericin B alone
- Oral formulation only:
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Flucytosine: side effects & toxicities
- Major toxicities are bone marrow suppression and GI toxicity
- Toxicity is dose and duration dependent
- Toxicity likely due to 5-fluorouracil which is produced from flucytosine by bacteria in gut lumen!!:
- Flucytosine is renally cleared and must be dose-adjusted in azotemic patients!!:
- Since flucytosine is commonly combined with amphotericin B, renal impairment caused by amphotericin B may increase flucytosine levels and worsen toxicity
- Monitoring flucytosine levels is helpful:
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Antifungal peptides
- Echinocandins: inhibition of fungal beta(1,3)-glucan synthase – depletion of glucan, which is a fungal cell wall constituent
- BROAD SPECTRUM
- Target growing tips of Aspergillus fumigatus hyphae; candidiasis
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Echinocandins three names
- Caspofungin
- Micafungin
- Anidulafungin
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Echinocandins: administration and toxic effects
- Excellent toxicity profile:
- Low incidence of infusion-related events: single case of anaphylaxis with caspofungin
- IV formulations only
- No known nephrotoxicity
- Liver enzyme changes are rare
- Echinocandins used with cyclosporin A can cause reversible liver enzyme abnormalities!:
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Echinocandins: candidiasis
- Potentially cidal in vitro
- Excellent activity against clinical isolates – including azole-resistant: cases of echinocandin-resistant candida species have been reported
- Effective in mucosal candidiasis and candidemia
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