involves internal organs; primary vs. opportunistic (AIDS, antibiotic use)
Allergic mycoses
affect lungs or sinuses; pts may have chronic asthma, CF or sinusitis
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
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)
Site of action of selected antifungals: Cell membrane
polyenes, azoles, allylamines
Site of action of selected antifungals: Cell Wall
Glucan synthesis inhibitors (echinocandins)
Site of action of selected antifungals: DNA Synthesis
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
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)
Candida albicans
54% of all bloodstream candida infxns; yeast cells and pseudohyphae in material from oral cavity; KOH preparation w/phase contrast microscopy
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
Fluconazole: Spectrum
C. albicans and Cryptococcus neoformans (other candida have resistance)
Fluconazole: Pharmokinetics
IV and PO; bioavailability 90%; >90% excreted unchanged thru kidney; weaker inhibitor of -3A4 than itra- or keto-; Inhibitor of CYP2C9
Fluconazole: Place in Therapy
oropharyngeal, esophageal, and vaginal candidiasis; Meintenance for cryptococcal meningitis; Systemic fungal infxn (candidemia, peritonitis); Prophylaxis in BMT pts
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
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)
Clinical Resistance is a Multifactorial Issue: Host
immune status, site of infxn, severity of infxn, foreign devices, noncompliance w/drug regimen
Clinical Resistance is a Multifactorial Issue: Fungus
initial MIC, cell type (yeast/hyphae), genomic stability, biofilm production, population bottlenecks
Clinical Resistance is a Multifactorial Issue: Drug
target enzyme modification, ergosterol byosynthetic pathway, efflux pumps, drug import
Itraconazole: spectrum
(broader than fuconazole); Aspergillus, Blastomyces, Histoplasma, Cryptococcus neoformans, Candida (incl fluconazole-resistant C. glabrata and C. krusei)
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)
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
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%)
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
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
Antifungal Agents: Polyenes
Amphotericin B, Nystatin
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
Amphotericin B: spectrum
the "big gun" - aspergillosis, blastomycosis, candidiasis, coccidiomycosis, cryptococcus, histoplasmosis, mucor; NOT: fusarium, C. lusitaniae
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
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
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.
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
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
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)
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
Ampotericin B: drug interactions
drugs which potentiate sodium loss or nephrotoxicity should be avoided (cyclosporine, aminoglycosides, foscarnet, pentamidine); antineoplastic agents (cisplatin, nitrogen mustards)
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
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
Echinocandins: Disadvantages
limited spectrum of activity; IV only; fungistatic vs. aspergillus
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)
Echinocandins: Spectrum of activity - Very Active
low MIC but w/o fungicidal activity in most cases (C. parapsilosis/gulliermondii/lusitaniae; A. fumigatus/flavus/terreus)
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)
Echinocandins: Spectrum of activity - inactive
no intrinsic activity; (Zygomycetes, Cryptococcus neoformans; Fusarium spp.; Trichosporon spp.)
Echinocandins: dosing
IV only; adjust in severe hepatic dysfunction; No renal penetration
Echinocandins: major adverse effects
usu infusion related (IV site irritation; fever, headache, flushing, erythema, rash ==> associated w/ histamine release)
targets cell MEMBRANE; inhibits CYP450 responsible for ergosterol synth; damages membrane growth; variable activity, potency and spectrum
Antifungal recap: Caspofungin
targets cell WALL; inhibits glucan synthesis; disrupts cell-wall structure; broad spectrum antifungal activity; potential for additive effects in combo therapy
Antifungal Agents: Flucytosine - MOA
anti-metabolite type of drug; DNA/RNA sythesis - rapid conversion of 5-FC to 5-FU in susceptible fungal cells
Flucytosine - Major adverse effects
bone marrow toxicity; monitor blood levels when used in combo w/Amphotericin B
Flucytosine - Place in therapy
monotherapy; now limited; rapid development of resistance; candidiasis/cryptococcus/aspergillus? ==> in combo w/amphotericin B of fluconazole
Current Antifungal Treatment Options - Amphotericin B
"gold standard" for efficacy; wide variety of acute and chronic side effects (nephrotoxicity even with lipid formulations)
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
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
CADD 2 Honors
