Antifungal Agents Flashcards
What is the most common fungal pathogen?
candida
What are fungal pathogens?
candida, aspergillus, zygomycetes, endemic fungi, cryptococcus
What does candida cause?
mild infections such as oropharyngeal or esophgeal candidiasis, uncomplicated candiduria, and vulvovaginal candidiasis
serious invasive diseases such as catheter-associated infections and disseminated disease (invasive candidiasis refers to severe forms of disease)
What are risk factors for invasive candidiasis?
prolonged stay in ICU; central venous catheters; prolonged therapy with broad spectrum antibacterial agents; receipt of parenteral nutrition; recent surgery; hemodialysis; DM
Increased mortality if empiric antifungal therapy is delayed by how many hours?
12 hours
What is aspergillus?
mold ubiquitous in the environment
primarily causes disease in immunocompromised hosts (neutropenia)
pulmonary system most common infection
definitive diagnosis requires positive culture from sterile site but can also use histologic/radiologic evidence in high-risk pt with negative cultures
What are zygomycetes?
rhizopus, absidia, mucor, rhizomucor
most commonly seen as sinus infection
risk factors: DM, immunosuppression!, penetrating injuries from natural disasters
definitive diagnosis: tissue invasion on histopathologic exam with or without microbiologic evidence
What is endemic fungi?
may cause disseminated disease via primary pulmonary infection
higher risk in pts with suppressed cell-mediated immunity
histoplasma capsulatum and blastomyces species found in IN
What is cryptococcus?
species found in IN: cryptococcus neoformans
encapsulated yeast that primarily affects the CNS and respiratory tract
more common in pts who are infected with HIV, have received organ transplants, or high-dose corticosteroids
What is the spectrum of activity of amphotericin B?
1st line: cryptococcus, blastomyces, histoplasma, mucor
commonly used as initial agent in systemic invasive fungal infections such as histoplasmosis/blastomyces and cryptococcal meningitis
Facts about amphotericin B
poorly absorbed after PO administration - requires IV
not appreciably metabolized (just naturally goes away)
renal and hepatic impairment and hemodialysis do NOT affect drug clearance (no dose adjustments)
lipid formulations –> 80-90% reduction in kidney concentration
What is the dosing for amphotericin B?
deoxycholate: usual 0.5-1 mg/kg/day (fewer adverse events if administered as continuous infusion over 24h)
liposomal: most commonly 3-5mg/kg daily
lipid complex: 5mg/kg daily
What are the adverse effects of amphotericin B?
infusion related reactions: pretreat with acetaminophen, antihistamines
nephrotoxicity - can cause increase in SCr and BUN
electrolyte abnormalities: hypokalemia, hypomagnesemia
anemia
How to prevent nephrotoxicity in amphotericin B?
0.5-1L normal saline over 30 min before AMB and 0.5-1L normal saline after completion of infusion; hydration!
What are facts about flucytosine?
great bioavailability
penetrates into CSF - main use is combo therapy with amphoB for cryptococcal meningitis
TDM to adjust dose: goal peak concentration 70-80 mcg/mL, trough concentrations 20-40 mcg/mL
85-95% excreted unchanged in urine (renally dose adjusted)
What is the spectrum of activity of flucytosine?
1st line for cryptococcus
candida
What is the dosing of flucytosine?
25 mg/kg/dose po q6h
What are the adverse effects of flucytosine?
GI
hematologic: bone marrow suppression (because it’s converted to 5-FU)
monitor: CBC, platelets, SCr, BUN
Ketoconazole
metabolized by the liver
not renally dose adjusted!
What are the adverse effects of ketoconazole?
GI, hepatotoxicity, endocrine (gynecomastia, decreased libido, oligospermia, loss of hair, menstrual irregularities)
What is the clinical use of ketoconazole?
shoule never be used orally for first-line therapy of any fungal infection due to risk of hepatotoxicity and drug interactions
mostly used topically for tinea infections
What is the spectrum of activity of ketoconazole?
candida albicans, cryptococcus, histoplasma
Fluconazole
bioavailability >90%
decent CSF concentration
excreted unchanged in urine - dose reduce in renal insufficiency
dosing based on TOTAL body weight
inhibitor of CYP2C9 and CYP3A4
What is the clinical use of fluconazole?
1st line for invasive candidiasis: if C. albicans - 800mg (12mg/kg) loading dose, then 400mg (6mg/kg) daily; if C. glabrata - 800mg daily (loading dose 1200-1600mg)
noninvasice candidiasis, prophylaxis in BMT, cryptococcal meningitis
What are the adverse effects of fluconazole?
QTc prolongation!!!
HA, nausea, anorexia, adrenal insufficiency, elevation of hepatic transaminases
What is the spectrum of activity of fluconazole?
1st line: candida albicans, candida parapsilosis, candida tropicalis, candida lusitaniae, coccidioides
cryptococcus
Itraconazole
metabolized by CYP450 3A4 isoenzyme
active metabolite: hydroxyitraconazole
clearance decreases with higher doses due to saturable hepatic metabolism
no dose adjustment for renal dysfunction
absorption dependent on gastric acidity: capsules better absorbed with meal or acidic cola; oral solution better absorbed in fasting state (not affected by gastric acidity)
What are the clinical uses of itraconazole?
1st line: histroplasmosis - 200mg PO TID x 3days, then 200mg PO BID; blastomycosis
What are the adverse effects of itraconazole?
hepatotoxicity, congestive heart failure (boxed warning), QTc prolongation
contraindicated in pregnancy and CHF
serum trough itraconazole concentrations > 0.5-1 mcg/mL; troughs >1.5 mcg/mL combined itraconazole and hydroxyitraconazole associated with efficacy, >3 mcg/mL –> increased AEs
What is the spectrum of activity of itraconazole?
1st line: blastomyces and histoplasma
C. albicans, C. parapsilosis, cryptococcus, coccidioides, aspergillus
Posaconazole
oral suspension - absorption affected by gastric pH
delayed release tabs - preferred oral formulation, absorption not affected by gastric pH
both better absorbed when taken with food
IV formulation contains cyclodextrin - AVOID if CrCl < 50mL/min
What are the adverse effects of posaconazole?
QTc prolongation!!
N/V/D, abdominal pain, increased AST/ALT/bilirubin, hypokalemia, rash, pseudohyperaldosteronism
What is the spectrum of activity of posaconazole?
C. albicans, C. parapsilosis, C. lusitaniae, cryptococcus, blastomyces, histoplasma, coccidioides, aspergillus, mucor
Voriconazole
significantly metabolized by CYP450 isoenzymes (2C19, 2C9, 3A4)
no dose adjustment necessary for ORAL dosing; AVOID IV if ClCr < 50mL/min due to accumulation of vehicle
absorption not affected by H2 antagonists, PPI, antacids
What is the clinical use of voriconazole?
invasive aspergillosis!
candidemia and other deep tissue candida infections, esophageal candidiasis
dosing based on ideal body weight of adjusted body weight
What are the adverse effects of voriconazole?
visual disturbances!, elevated liver function tests, QTc prolongation, phototoxic skin reactions, diffuse painful periostitis
What is the spectrum of activity of voriconazole?
very broad
1st line: aspergillus
C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, C. krusei, C. lusitaniae, C. auris, cryptococcus, blastomyces, histoplasma, coccidioides
Isavuconazole
good oral bioavailability
no dosage adjustment for renal impairment or ESRD
IV formulation does NOT contain cyclodextrin
What is the clinical use of isavuconazole?
invasive aspergillus or mucor (usually last line therapy)
this is pro-drug
What are the adverse effects of isavuconazole?
N/V/D, HA, hepatic, infusion related reactions (d/c if occurs), hypokalemia, hypersensitivity and severe skin reactions
does NOT cause QTc prolongation (can actually shorten)! - use in pts with prolonged QTc
What are the drug interactions of isavuconazole?
overall considered to be the least DI in the azole family
contraindicated with familial short QT syndrome
What is the spectrum of activity of isavuconazole?
very broad
C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, C. krusei, C. lusitaniae, C. auris, cryptococcus, blastomyces, histoplasma, coccidioides, aspergillus, mucor
Overall was are the class adverse effects of azoles?
hepatic dysfunction
QTc prolongation (except isavuconazole)
GI intolerance
many drug interactions - because of hepatic elimination
What drug has the greatest spectrum of activity?
isavuconazole > voriconazole > posaconazole > itraconazole > fluconazole > ketocontazole
