EXAM III Antifungals Flashcards
Fungus Types
Kingdom, Eukaryotic, Heterotrophs, Acrophyllus
Yeasts, Molds
Present widely
Approx 300 of pathogenic fungi
- Candida spp.*
- Cryptococcus spp.*
- Aspergillus spp.*
Fungal infections
Increasing number of immunocompromised PTs
Transplants
HIV/AIDS
Autoimmune conditions requiring immunosuppression
Cystic fibrosis
Corticosteroid/antibiotic use
Chemo
Can occur in immunocompetent PT as well
Route of transmission
Respiratory
Traumatic implantation
Direct contact
Fungal cell
Fungus Structure
Antifungal Agents
Allylamines - Topical agents
Polyenes
Azoles
Echinocandins
Misc - Flucytosine
Allylamines
Topical agents
Indication: Tinea cosporis, tinea pedis, tinea cruris, onychomycosis (terbinafine)
MOA: Inhibition of squalene epoxidase -> reducing fungal cell membrane ergosterol synthesis
Agents:
- Terbinafine (Lamisil) - Also PO*
- Butenafine*
- Naftifine*
- Amorolfine*
- * The Fines!*
Terbinafine
Renally eliminated
Half-life: 36 Hrs
Terminal Half-Life 200-400 Hrs -> prolonged elimination from skin and adipose
Dose:
- Fingernails - 250mg PO QD x6 W*
- Toenails - 250 mg QD x12 W*
- Tinea - 250 mg PO QD x2 W*
Monitoring
SCr, LFTs (at baseline & throughout treatment), CBC if > 6 weeks tx in immunodeficient PTs
Azoles
Imidazoles and triazoles
MOA: Inhibition of 14 alpha-demethylase which converts lanosterol to ergosterol = disruption in cell membrane synthesis; block steroid synthesis in humans
Azoles: Imidazoles
Clotrimazole
Ketoconazole
Miconazole
Econazole
Mebendazole
Oxiconazole
Sertaconazole
Thiabendazole
Imidazoles CloK ME MOST
Azoles: Imidazoles Indications
Mostly Topical agents
Indications:
- Tinea* cotporis
- Tinea pedis*
- Tinea* cruris
- Oropharyngeal candidiasis*
- Vulvovaginal candidiasis*
Ketoconazole
Effective against Candida spp., blastomycosis, histoplasmosis (high failure rates)
Excreted in feces
Half-Life: 8 Hrs
CYP450 3A4 substrate -> CYP inhibition = drug interactions
Needs Acidic gastric pH for absorption - think drug interactions w/ H2RA, PPIs, Antacids
Note poor distribution into CSF and eye
Dose:
- 200-4– mg PO QD*
- Contraindicated in PTs w/ hepatic impairment*
- Available in many forms*
Azoles: Triazoles
Itraconazole
Fluconazole
Isavuconazole
Voriconazole
Posaconazole
Triazoles IF I VP
Think for systemic invasive fungal infections
Azoles: Triazoles Details
MOS: Inhibition of CYP450 and sterol C-14alpha-demethylation
- THink drug interaction*
- All azoles inhibit CYP3A4 (Itra&posa > fluc, vori, & isavuconazole)*
Primary Fungistatic
Newer Azoles = less hormonal inhibition, broader spectrum, less toxic, better tissue distribution
Spectrum of activity:
- Fluconazole &itraonazole: Candida, Aspergillus, Fusarium, Scedosporium, and other molds*
- Posaconazole and Isavuconazole also cover mucormycosis*
Triazoles - Spectrum of Activity
Fluconazole
Indication
- Candidiasis: invasive (oroesophageal/urogenital/vulvovaginal); prophylaxis in BMT recipients/TXT PTs*
- Cryptococcus: consolidation phase*
80% excreted unchanged in urine; high urine levels
Half-Life: 30Hrs; prolonged in renal impairment (98-125 Hrs)
CNS penetration
Minor inhibition of CYP 3A4/moderate inhibition of CYP 2C9
Dose:
- Depends on indication*
- 100-800mg QD*
- Needs renal adjust*
Itraconazole
Indication:
- Candidiasis: oropharyngeal and esophageal*
- Maybe a step-down therapy in Aspergillosis (not first line)*
99% protein bound
35% renally eliminated
Half-Life 34-42 Hrs
Dose:
- Available in capsules or solution -> cannot be interchanged*
- Capsules need to be given w/ meal*
- Solution* should be given on an empty stomach and is preferred formulation
- 200-600mg QD*
- Requires Renal elimination*
Voriconazole
Indication
- Resistant Candida infections*
- Aspergillosis*
- Other mold infections*
2% renal elimination
Half-Life is dose-dependent, non-linear kinetics
95% bioavailability, but :
- Can be unpredictable*
- Reduced w/high fat meal*
Large Vd with good CNS penetration
Substrate and inhibitor of CYP3A4/2C9/2C19 -> Drug interactions
Voriconazole Dosing
Dose:
IV: load 6mg/kg Q12H x2 then 4mg/kg Q12H
PO:
- Weight-Dependent*
- >40kg: 200-300mg Q12H*
- <40mg 100-150mg Q12H*
- Admin 1 Hr before or after meal*
Monitoring
target Cmin 1-5.5mg/L, for severe infections >2mg/mL
Level > 5mg/L=CNS toxicity
SCr, electrolytes, LFTs, ophthalmic exam if therapy > 4 weeks
Side effects
N/V/D. liver dysfunction
Visual abnormalities
HA
hepatotoxicity
Posaconazole
Indication:
- Resistant Candida infections*
- Aspergillosis*
- Mucorales and other mold infections*
<1% eliminated in urine
Half-Life: 26-35 Hrs
Extensive distribution and penetration into tissues/ potentially therapeutic CSF levels
Potent inhibitor of CYP3A4
Inhibitor and substrate of P-glycoprotein
DEC absorption w/ PPis, H2RA
Oral bioavailability >90% w/high fat meal
Posaconazole Dosing
Dose:
- Indication dependent*
- Tablet: QD delayed release*
- Suspension: 300-400mg PO TID -QID*
- IV: 300mg Q12H x1 day then QD*
- Caution w/ oral admin-> slow onset*
No renal adjustment
Monitoring
SCr, electrolytes, LFTs
Side Effects: GI, HA, rare hepatotoxicity, QTc prolongation, hemolytic uremic syndrome
Isavuconazole
Indication:
- Invasive Aspergillosis*
- Mucormycosis*
Admin as pro-drug; Isavuconazonium
Cleared primarily via Fecal excretion
Half-Life: 130 Hrs
Substrate of CYP3A4
Contraindicated with potent 3A4 inhibitors and inducers
Isavuconazole Dosing
Dose:
- Loading dose: 372mg IV/PO Q8H x2 days then QD*
- 372mg=200mg of isavuconazole*
- No dose adjust in hepatic/renal impairments*
Contraindicated in familial short QT syndrome
DDIs: Inhibits CYP3A4, P-glycoprotein, and OCT-2
Side Effects: GI, hypokalemia, elevated LFTs, HA
Monitor: LFTs
Polyenes
MOA: Bind w/ sterols in the fungal cell membrane (principally ergosterol), leads to the cell contents leak out ultimately cell death.
Agents:
- Nystatin*
- Amphotericin B*
Nystatin
Indication
Candida spp only
Minimal Systemic absorption -> almost entirely excreted in feces unchanged
Too toxic for systemic admin
Dose:
- Oropharyngeal candidiasis: 4-6 ml PO QID; retain in mouth as long as possible*
- Intestinal candidiasis: 5-10ml PO TID*
- Also admin topically*
Amphotericin B
Amphotericin B Dosing
Exact routes for elimination and metabolism
>90% protein bound
Terminal Half-Life:>15 days
Dose:
- AmB-d: 0.3-1.5 mg/g/day*
- L-AmB: 3-5mg/kg/day*
- No dose adjust*
Amphotericin AmB-d
Nephrotoxic
ARF in 50% of PTS
Infusion-related reaction
- Pre-medicate w/ APAP or IBU, diphenhydramine +/- steroids*
- Rigors: meperidine*
Side Effects:
- Thrombophlebitis, cardiac arrhythmias, rash*
- Dose-dependent decrease in GFR (vasoconstrictive effect on renal arterioles)*
- Decrease erythropoietin production*
- Electrolyte derangement*
Monitor:SCr, BUN, electrolytes, CBC, LFTs
Amphotericin B L-AmB
L-AMB
- Less toxicities vs AmB-d*
- Less nephrotoxic*
- Reduced frequency and severity of infusion-related reactions*
Higher Cmax and larger AUC
Higher tissue concentrations vs other AmB formulations
Hepatotoxicity: INC alk, phos, and conjugated bili
