Antifungals
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| Superficial mycoses | affect hair, skin, nails; do not penetrate body, few symptoms; ex: athletes' foot and thrush
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| Subcutaneous mycoses (soil/vegetation in tropical areas) | affects muscle and CT immediately below skin; enters skin thru injury, esp feet
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| Systemic (invasive) mycoses | involves internal organs; primary vs. opportunistic (AIDS, antibiotic use)
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| Allergic mycoses | affect lungs or sinuses; pts may have chronic asthma, CF or sinusitis
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| Fungal vs. mammalian cells | 1. Fungal Cell Wall is a target for drugs; Glucan and chitin for structural rigidity; mannoproteins; 2. Cell Membrane - ergosterol instead of cholestrol
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| 3 primary mechanisms of action for antifungal drugs | 1. Cell membrane (ergosterol); 2. DNA Synthesis (some compounds selectively activated by fungi; arresting DNA synth); 3. Cell Wall (not present in mammalian cells)
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| Site of action of selected antifungals: Cell membrane | polyenes, azoles, allylamines
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| Site of action of selected antifungals: Cell Wall | Glucan synthesis inhibitors (echinocandins)
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| Site of action of selected antifungals: DNA Synthesis | Flucytosine
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| Antifungal Agents: Azoles | Fluconazole (Diflucan); Itraconazole (Sporanox); Ketoconazole (Nizoral); Voriconazole (Vfend); Posaconazole
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| Antifungal Agents: Allylamines | Terbinafine
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| Azoles: MOA | inhibit fungal CYP450 3A dependent enzyme: 14-alpha-demethylase (synthesizes ergosterol); By depeting ergosterol/accumulating toxic sterols/damaging cytoplasmic membrane/no growth; spectrum/potency vary; not completely selective for fungal CYP450
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| Allylamines: MOA | nhibit fungal CYP450 3A dependent enzyme: squalene oxidase
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| Azole Antifungals for Systemic Infections | Imidazole (ketoconazole (Nizoril)); Triazoles (Itraconazole (sporonax), Fluconazole (Diflucan)); 2nd generation triazole (Voriconazole (Vfend))
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| Ketoconazole | rarely used; PO, shampoo; mucosal infxns only d/t poor absorption; hepatotoxic; inhibits CYP450 for testosterone/adrenal cortisol synth (gynecomastia, oligospema, dec libido); absorption depends on pH (give w/cola or fruit juice); hepatic/bile/kidney elim
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| Ketoconazole: Drug Interactions | SEVERE rxns; potent inhibitor of CYP450; Rifampin and Phenytoin dec ketoconazole levels; K increases cyclosporine, warfarin, CCsteroid and threophylline levels; drugs that inc gastric pH dec blood levels of K (antacids/omeprazole/H2 blockers)
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| Candida albicans | 54% of all bloodstream candida infxns; yeast cells and pseudohyphae in material from oral cavity; KOH preparation w/phase contrast microscopy
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| Fluconazole | major drug against Candida sp (albicans, tropicalis, parapsilosis, and Cryptococcus neoformans); DOES NOT cover: can Candida krusei, +/- Candida glabrta; aspergillus sp and other molds
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| Fluconazole: Spectrum | C. albicans and Cryptococcus neoformans (other candida have resistance)
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| Fluconazole: Pharmokinetics | IV and PO; bioavailability 90%; >90% excreted unchanged thru kidney; weaker inhibitor of -3A4 than itra- or keto-; Inhibitor of CYP2C9
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| Fluconazole: Place in Therapy | oropharyngeal, esophageal, and vaginal candidiasis; Meintenance for cryptococcal meningitis; Systemic fungal infxn (candidemia, peritonitis); Prophylaxis in BMT pts
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| Fluconazole: Major Adverse Effects | Nausea/vomiting; rash (high dose and AIDS pts; asymptomatic inc in LFTs); Drug interactions: inc of phenytoin/cyclosporin/rifabutin/varfarin/zidovudine; Rifampin reduced fluconazole levels to 1/2
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| Fluconazole: Resistance | 1* Resistance (seen in immuno deficient pts)(selection of resistant sp/subpop); 2* resistance (pts w/AIDS w/recurrent oropharyngeal candidiasis and long term therapy - genetic mutation/upregulation of efflux pumps)
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| Clinical Resistance is a Multifactorial Issue: Host | immune status, site of infxn, severity of infxn, foreign devices, noncompliance w/drug regimen
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| Clinical Resistance is a Multifactorial Issue: Fungus | initial MIC, cell type (yeast/hyphae), genomic stability, biofilm production, population bottlenecks
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| Clinical Resistance is a Multifactorial Issue: Drug | fungistatic nature, dosing, pharmokinetics, drug-drug interactions
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| Mechanisms of Antifungal Resistance | target enzyme modification, ergosterol byosynthetic pathway, efflux pumps, drug import
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| Itraconazole: spectrum | (broader than fuconazole); Aspergillus, Blastomyces, Histoplasma, Cryptococcus neoformans, Candida (incl fluconazole-resistant C. glabrata and C. krusei)
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| Itraconazole: pharmokinetics | PO (capsule and sol'n), IV; variable oral absorption (capsule w/food; sol'n on empty stomach); Does NOT cross BBB; potent inhibitor of -3A4 (many drug interactions)
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| Itraconazole: Place in Therapy | 2nd line (after Amphotericin) for: Blastomycosis, Histoplasmosis (not in CNS), Aspergillosis; empiric therapy in Febrile Neutropenic pts; oral/esophageal candidiasis; onychomycosis
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| Itraconazole: Major Adverse Effects | taste disturbances, nausea/vomiting; osmotic diarrhea (esp doses >400 mg/day) difficult long-term compliance; rash; hepatotoxicity; avoid pts w/ventricular dysfunction
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| Voriconazole: spectrum | similar to itraconazole, but: more active against: Aspirgillus, C. glabrata, C. krusei; Active against: Fusarium, Scedosporium
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| Voriconazole: pharmokinetics | IV, PO; metabolized by liver (CYP2C19 - genetic variation w/races, 2C9, 3A4) - many drug interactions
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| Voriconazole: Place in Therapy | invasive Aspergillosis; Candida infxns (skin, abdomen, bladder, kidney); Refractory Fusarium; Scedosporium infxn
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| Voriconazole: Major adverse effects | Visual disturbances (30%) - dec vision/photophobia/altered color perception/ocular discomfort; moreso w/IV than PO; no structural damage to retina; effects may be intensified by hallucinations (2-5%)
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| Triazoles in a nutshell: Fluconazole | C. albicans/tropicalis/+/-glabrata; No aspergillus; >90% oral bioavailable; 80% renal clearance; halflife - 24hrs; CNS penetration; weak CYP3A4 inhib; N&V, hepatic side effects
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| Triazoles in a nutshell: Itraconazole | C. albicans/tropicalis/+/- glabrata/Aspergillus! oral bioavail <25%/solution bioavail 20-60%; hepatic 3A4 clearance; halflife - 24-30hrs; poor CNS penetration; strong CYP3A4 inhib; N&V diarrhea (sol'n) hepatic, CHF
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| Triazoles in a nutshell: Voriconazole | most candida/aspergillus/fusarlum; NOT zygomycoses; >90% bioavail; hepatic clearance 2C19/3A4; halflife - 6-24hrs; CSF penetration; mod-severe CYP3A4 inhib; N&V, visual disturbances, hepatotoxicity, rash
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| Terbinafine (Lamisil) | PO/topical; dermatophytes, cadida (incl fluconazole-resistant strains); Primary use: onchyomycosis of nails orally; used OTC for athlete's foot; GI effects, hepatic injury/failure
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| Antifungal Agents: Polyenes | Amphotericin B, Nystatin
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| Amphotericin B: MOA | binds ergosterol in fungal membrane to inc permeability; It may bind to other sterols (incl cholesterol in human cells) resulting in poor tolerability
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| Amphotericin B: spectrum | the "big gun" - aspergillosis, blastomycosis, candidiasis, coccidiomycosis, cryptococcus, histoplasmosis, mucor; NOT: fusarium, C. lusitaniae
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| Amphotericin B: toxic vs. less toxic forms | dextrose micelle suspension leads to renal damage; LESS TOXIC Preps: Liposomal amphotericin B, Amphotericin B colloidal dispersion, Amphotericin B lipid complex
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| Lipid Amphotericin B Formulations: ABLC | composed of amphotericin B complexed with dymyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol. The configuration of this complex is ribbon-like. Its trade name is AbelcetT
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| Lipid Amphotericin B Formulations: ABCD | composed of amphotericin B complexed with cholesteryl sulfate. It is a disk-like structure. Its trade name is Amphotec™. Amphocil is an IV form.
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| Lipid Amphotericin B Formulations: L-AMB | complexed with hydrogenated soy phosphatidylcholine, distearoylphosphatidylglycerol, & cholesterol. Unlike the other lipid formulations of amphotericin B; a true liposome composed of unilamellar lipid vesicles. tradename: Ambisome
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| Amphotericin B: Pharmokinetics | IV only; drug accumulates in tissues and is slowly released (kidney/lung/liver/spleen well and CSF/eye/bone poorly); Dose NOT altered to dec elimination in kidney dysfxn
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| Amphotericin B: Major Adverse Effects | Delayed toxicity!! Renal Toxicity: Inc renal vascular resistance (drop in GFR) and Increased tubular permeability (wasting of potassium and magnesium); fever, chills, hypotension (pretreat w/benadryl, APAP, hydrocortisone - meperidine indication)
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| Ampotericin B: methods to combat nephrotoxicity | sodium loading ==> blunt the vasoconstriction and tubular-glomerular feedback (admin 500-1000mL of NaCl before/after infusion to prevent sodium depletion from inc cellular permeability
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| Ampotericin B: drug interactions | drugs which potentiate sodium loss or nephrotoxicity should be avoided (cyclosporine, aminoglycosides, foscarnet, pentamidine); antineoplastic agents (cisplatin, nitrogen mustards)
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| Nystatin | topically, vaginally, orally (oral thrush)
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| Antifungals: Echinocandins (glucan synthesis inhibitors) | Caspofungin, Micafungin
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| Echinocandins: MOA | b(1,3)-D-glucan is essential to cell wall integrity of susceptible Aspergillus and Candida spp; inhibiting its synthesis in regions of active cell growth results in cell wall permeability
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| Echinocandins: Advantages | activity against most common fungal pathogens; no adverse events d/t MOA; min potential for adverse effects (no nephro/hepatotoxicity); no CYP450 drug interactions; unlikely azole x-resistance
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| Echinocandins: Disadvantages | limited spectrum of activity; IV only; fungistatic vs. aspergillus
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| Echinocandins: Spectrum of activity - Highly active | low MIC (min inhib conc) w/fungicidal activity and good in-vivo activity (C. albicans/glabrata/tropicalis/krusei/kefyr; P. jiroveci (carinii)
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| Echinocandins: Spectrum of activity - Very Active | low MIC but w/o fungicidal activity in most cases (C. parapsilosis/gulliermondii/lusitaniae; A. fumigatus/flavus/terreus)
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| Echinocandins: Spectrum of activity - Some activity | detectable activity may have therapeutic potential for man (in combo w/other drugs); (C. immitis; B. dermatididis; Scedosproium spp; P. variotti; H. capsulatum)
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| Echinocandins: Spectrum of activity - inactive | no intrinsic activity; (Zygomycetes, Cryptococcus neoformans; Fusarium spp.; Trichosporon spp.)
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| Echinocandins: dosing | IV only; adjust in severe hepatic dysfunction; No renal penetration
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| Echinocandins: major adverse effects | usu infusion related (IV site irritation; fever, headache, flushing, erythema, rash ==> associated w/ histamine release)
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| Antifungal recap: Amphotericin B | targets cell MEMBRANE; binds ergosterol causing cell death; potent, broad-spectrum activity
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| Antifungal recap: Azoles | targets cell MEMBRANE; inhibits CYP450 responsible for ergosterol synth; damages membrane growth; variable activity, potency and spectrum
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| Antifungal recap: Caspofungin | targets cell WALL; inhibits glucan synthesis; disrupts cell-wall structure; broad spectrum antifungal activity; potential for additive effects in combo therapy
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| Antifungal Agents: Flucytosine - MOA | anti-metabolite type of drug; DNA/RNA sythesis - rapid conversion of 5-FC to 5-FU in susceptible fungal cells
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| Flucytosine - Major adverse effects | bone marrow toxicity; monitor blood levels when used in combo w/Amphotericin B
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| Flucytosine - Place in therapy | monotherapy; now limited; rapid development of resistance; candidiasis/cryptococcus/aspergillus? ==> in combo w/amphotericin B of fluconazole
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| Current Antifungal Treatment Options - Amphotericin B | "gold standard" for efficacy; wide variety of acute and chronic side effects (nephrotoxicity even with lipid formulations)
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| Current Antifungal Treatment Options - Azoles | Older agents: inconsistent efficacy in Aspergillus; Newer Triazoles: efficacious against Aspergillus; increasing resistance to candidal infxn by non-albicans sp; numerous drug interactions associated w/CYP450
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| Antifungals - Safety Recap | activity of amphotericin B in human/fungal cells may underlie serious toxicities incl nephrotoxicity; weaker effects in humans favor tolerability of triazole antifungals; unique specific MOA of caspofungin results in low potential for mech-based toxicity
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