Antifungal Flashcards
Allylamines Agents
Terbinafine
Amoroifine
Naftifine
Butenafine
Allylamines MOA
inhibits the enzyme squalene epoxidase, required for ergosterol synthesis (prevents formation of steroid –> leakage)
Polyenes Agents
Nystatin
Amphotericin B
Polyenes MOA
binds with sterol in the fungal cell membrane (ergosterol) and causes cell content to leak out and the cell dies
Allylamines Coverage
Topical agents Piedra Tinea Nigra Tinea Capitis Favus Pityriasis
Nystatin
Covers Candida Species Only
Minimal Side effects
Swish & Spit or Shampoo
Orally –> poorly absorbed from the GI tract; too toxic to be used systemically
Topically –> not absorbed from intact skin or mucous membrane
Amphotericin B Agents
Amphotericin B deoxycholate
Amphotericin B colloidal dispersion
Amphotericin B lipid complex
Liposomal Amphotericin B
Amphotericin B MOA
Binds to ergosterol within the fungal cell membrane
Results in depolarization of the membrane
Forms Pores: leakage of intracellular content
Exhibits concentration dependent killing
Amphotericin B Coverage
Broad Spectrum antifungal (Empiric therapy)
Active against most molds and yeast
Not active against C. lusitanae, Fusarium, Tricosporon, Scedosporium
Amphotericin B deoxycholate
Distributes quickly out of the blood and into liver and other organs and slowly re-enters circulation (linger effects
Poor penetration: CNS, saliva, bronchial secretions, pancreas, muscle and bone
ADE: Glomerular nephrotoxicity ( dose-dependent decrease in GFR), tubular nephrotoxicity (K, Mg+, and bicarbonate wasting), decreased erythropoietin production, and acute reactions (chills, fevers, tachypnea, hypotension)
Amphotericin B deoxycholate Support management
Fluids (for hydration or hypotension)
Add potassium replacement (if hypokalemia)
Avoid concurrent nephrotoxic agents
Premed with acetaminophen, diphenhydramine or hydrocortisone (for fever/chills)
add heparin to the infusion to manage thrombophlebitis
Amphotericin B colloidal dispersion
acute infusion related reactions
Reduced rates of nephrotocicity compared to Amphotericin B deoxycholate
Amphotericin B lipid complex
Distributed into tissues more rapidly
Highest levels achieved in spleen, liver, and lungs
Lowest levels in lymph nodes, kidneys, heart, and brain
reduced frequency and severity of infusion related reactions
Reduced nephrotoxicity
Liposomal Amphotericin B
Higher Cmax and larger AUC
Higher concentration in liver, lungs, and spleen
lower concentrations in kidney, brain, lymph nodes, and heart
May achieve higher brain concentrations
Reduced frequency and severity of infusion related reactions
Reduced rate of nephrotoxicity
Azoles MOA
inhibit 14-alpha-demethylase which converts lanosterol to ergosterol, and is required in fungal cell membrane synthesis; also block steroid synthesis in humans
Imidazoles Agents
Miconazole Ketoconazole Butoconazole Clotrimazole Econazole Mebendazole Oxiconazole Sertaconazole Sulconazole Thiabendazole
Triazoles Agents
Fluconazole Isavuconazole Itraconazole Posaconazole Voriconazole
Imidazoles Coverage
Typically topical against:
Tinea corporis
Tinea cruris
Tinia pedis
Oropharyngeal candidiasis
Vulvovaginal candidiasis
Contact dermatitis
Vulvular irritationKetoconazole
Candidia species Blastomycosis Histoplasmosis (not immunocompromised) Coccidioidomycosis (not for meningitis or severely ill) Paracoccidioidomycosis INACTIVE against aspergillus needs acidic gastric pH for absorption Distributes into epidermis, synovial fluid, saliva, and lungs Poor distribution into CSF and eye Decrease dose for severe liver failure Can inhibit sterol synthesis in humans ADE
Ketoconazole ADE
GI distress
Rash
Increased LFTs
hepatitis –> can be fatal if not d/c
Dose-dependent inhibition of syntheis of testosterone –> impotence or gynecomastia
menstrual irregularities
alopecia
Dose-related decrease in cortisol synthesis
hypermineralocorticoid state –> HTN in long term use
Teratogenic in animals
Ketoconazole DDI
Antacids, H2 blockers, proton pump inhibitors, sucralfate decrease absorption of ketoconazole
Rifampin decreases ketoconazole
CYP inhibition: cyclosporine, warfarin, phenytoin
Fluconazole
Covers everything except: C.krusei, Aspergillus, Fusarium, Scedosporium, and zygomycetes
ADE: well tolerated, GI intolerance, Elevated LFTs, Rash
Isavuconazole
Covers Aspergillus and mucomycosis
ADE: GI, QTc shortening, Fatigue, Chest pain, hypokalemia, hypomagnesemia, nephrotoxicity, hypotension
DDI: VIa CYP 3A4
Itraconazole
Covers everything except: Fusarium, Scedosporium, and zygomycetes
Low coverage C. glabrata and C. krusei
ADE: C/I patients with CHF due to negative inotropic effects, QTc prolongation (other arrhythmias, hepatoxicity, rash, hypokalemia, GI tolerance
DDI: Strong inhibtor of CYP 3A4
Posaconazole
Covers everything except Scedosporium
ADE: hepatotoxicity, QTc prolongation, GI intolerance
metabolized via Glucuronidation
Voriconazole
Covers eveything except Scedosporium and zygomycetes
ADE: Visual/auditory disturbances, peripheral edema, rash, n/v/d, hepatotoxicity, headache, fever
Severe: SJS, liver failure, anaphalaxis, renal failure, QTc prolongation
Dose for
Cirrhosis
Renal impairment (CrCl<50ml/min use oral formulation to avoid accumulation)
DDI: many DDI
Echinocandin MOA
inhibit the synthesis of glucan in cell wall, probably via the enzyme 1,3- glucan synthase
Echinocandin Agents
Anidulafungin
Caspofungin
Micafungin
Echinocandin Coverage
Covers ALL candida and Aspergillus
Blastomyces & Coccidioides
Caspofungin DDI
NO CYP metabolism
CYP inducers reduce caspofungin levels
Cyclosporine –> increases AUC of caspofungin (monitor LFTs)
Tacrolimus –> reduces tacrolimus levels (monitor)
Micafungin DDI
Nifedipine increases AUC and Cmax of Nifedipine –> monitor BP
Sirolimus Increases concentration of Sirolimus (monitor)
Anidulafungin DDI
No DDI
Echinocandin ADE
well tolerated
infusion related reaction (fever, phlebitis)
GI intolerance
Hypokalemia
Hypomagnesium
Elevated LFTs
Caspofungin has higher frequency of liver related lab abnormalities and higher frequency of infusion related pain and phlebitis
Other Antifungal Agents
Flucytosine Griseofulvin Salicycic Acid Tinactin or Tolnaftate Potassium Iodide
Flucytosine MOA
converted by ctosine deaminase into 5-fluorouracil –> 5-fluorouridine triphosphate and incorporated into fungal RNA leading to miscoding. Also converted into 5-fluorodeoxyuridine monophosphate which interfers with DNA synthesis
Griseofulvin MOA
binds to polymerized microtubules and inhibits fungal mitosis
Flucytosine Coverage
Destributes into tissues, CSF, and bodily fluids Candida species except C. krusei Cryptococcus neoformans Aspergillus species Synergy with amphotericin B
Flucytosine Resistance
Loss of cytosine permease that permits flucytosine to cross the fungal cell membrane
Loss of any of the enzymes required to produce the active forms that interfere with DNA synthesis
RESISTANCE occurs frewuently and rapidly with flucytosine as MONOTHERAPY
Flucytosine ADE
Bone marrow suppression (dose-dependent) Hepatotoxicity (dose dependent) Enterocolitis Toxicities occur more commonly in patients with renal impairments Contraindicated in Pregnancy
