Antifungal Agents

Question 1

What is the most common fungal pathogen?

Answer 1

candida

Question 2

What are fungal pathogens?

Answer 2

candida, aspergillus, zygomycetes, endemic fungi, cryptococcus

Question 3

What does candida cause?

Answer 3

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)

Question 4

What are risk factors for invasive candidiasis?

Answer 4

prolonged stay in ICU; central venous catheters; prolonged therapy with broad spectrum antibacterial agents; receipt of parenteral nutrition; recent surgery; hemodialysis; DM

Question 5

Increased mortality if empiric antifungal therapy is delayed by how many hours?

Answer 5

12 hours

Question 6

What is aspergillus?

Answer 6

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

Question 7

What are zygomycetes?

Answer 7

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

Question 8

What is endemic fungi?

Answer 8

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

Question 9

What is cryptococcus?

Answer 9

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

Question 10

What is the spectrum of activity of amphotericin B?

Answer 10

1st line: cryptococcus, blastomyces, histoplasma, mucor
commonly used as initial agent in systemic invasive fungal infections such as histoplasmosis/blastomyces and cryptococcal meningitis

Question 11

Facts about amphotericin B

Answer 11

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

Question 12

What is the dosing for amphotericin B?

Answer 12

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

Question 13

What are the adverse effects of amphotericin B?

Answer 13

infusion related reactions: pretreat with acetaminophen, antihistamines
nephrotoxicity - can cause increase in SCr and BUN
electrolyte abnormalities: hypokalemia, hypomagnesemia
anemia

Question 14

How to prevent nephrotoxicity in amphotericin B?

Answer 14

0.5-1L normal saline over 30 min before AMB and 0.5-1L normal saline after completion of infusion; hydration!

Question 15

What are facts about flucytosine?

Answer 15

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)

Question 16

What is the spectrum of activity of flucytosine?

Answer 16

1st line for cryptococcus
candida

Question 17

What is the dosing of flucytosine?

Answer 17

25 mg/kg/dose po q6h

Question 18

What are the adverse effects of flucytosine?

Answer 18

GI
hematologic: bone marrow suppression (because it’s converted to 5-FU)
monitor: CBC, platelets, SCr, BUN

Question 19

Ketoconazole

Answer 19

metabolized by the liver
not renally dose adjusted!

Question 20

What are the adverse effects of ketoconazole?

Answer 20

GI, hepatotoxicity, endocrine (gynecomastia, decreased libido, oligospermia, loss of hair, menstrual irregularities)

Question 21

What is the clinical use of ketoconazole?

Answer 21

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

Question 22

What is the spectrum of activity of ketoconazole?

Answer 22

candida albicans, cryptococcus, histoplasma

Question 23

Fluconazole

Answer 23

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

Question 24

What is the clinical use of fluconazole?

Answer 24

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

Question 25

What are the adverse effects of fluconazole?

Answer 25

QTc prolongation!!! HA, nausea, anorexia, adrenal insufficiency, elevation of hepatic transaminases

Question 26

What is the spectrum of activity of fluconazole?

Answer 26

1st line: candida albicans, candida parapsilosis, candida tropicalis, candida lusitaniae, coccidioides cryptococcus

Question 27

Itraconazole

Answer 27

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)

Question 28

What are the clinical uses of itraconazole?

Answer 28

1st line: histroplasmosis - 200mg PO TID x 3days, then 200mg PO BID; blastomycosis

Question 29

What are the adverse effects of itraconazole?

Answer 29

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

Question 30

What is the spectrum of activity of itraconazole?

Answer 30

1st line: blastomyces and histoplasma C. albicans, C. parapsilosis, cryptococcus, coccidioides, aspergillus

Question 31

Posaconazole

Answer 31

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

Question 32

What are the adverse effects of posaconazole?

Answer 32

QTc prolongation!! N/V/D, abdominal pain, increased AST/ALT/bilirubin, hypokalemia, rash, pseudohyperaldosteronism

Question 33

What is the spectrum of activity of posaconazole?

Answer 33

C. albicans, C. parapsilosis, C. lusitaniae, cryptococcus, blastomyces, histoplasma, coccidioides, aspergillus, mucor

Question 34

Voriconazole

Answer 34

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

Question 35

What is the clinical use of voriconazole?

Answer 35

invasive aspergillosis! candidemia and other deep tissue candida infections, esophageal candidiasis dosing based on ideal body weight of adjusted body weight

Question 36

What are the adverse effects of voriconazole?

Answer 36

visual disturbances!, elevated liver function tests, QTc prolongation, phototoxic skin reactions, diffuse painful periostitis

Question 37

What is the spectrum of activity of voriconazole?

Answer 37

very broad 1st line: aspergillus C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, C. krusei, C. lusitaniae, C. auris, cryptococcus, blastomyces, histoplasma, coccidioides

Question 38

Isavuconazole

Answer 38

good oral bioavailability no dosage adjustment for renal impairment or ESRD IV formulation does NOT contain cyclodextrin

Question 39

What is the clinical use of isavuconazole?

Answer 39

invasive aspergillus or mucor (usually last line therapy) this is pro-drug

Question 40

What are the adverse effects of isavuconazole?

Answer 40

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

Question 41

What are the drug interactions of isavuconazole?

Answer 41

overall considered to be the least DI in the azole family contraindicated with familial short QT syndrome

Question 42

What is the spectrum of activity of isavuconazole?

Answer 42

very broad C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, C. krusei, C. lusitaniae, C. auris, cryptococcus, blastomyces, histoplasma, coccidioides, aspergillus, mucor

Question 43

Overall was are the class adverse effects of azoles?

Answer 43

hepatic dysfunction QTc prolongation (except isavuconazole) GI intolerance many drug interactions - because of hepatic elimination

Question 44

What drug has the greatest spectrum of activity?

Answer 44

isavuconazole > voriconazole > posaconazole > itraconazole > fluconazole > ketocontazole