4. Antifungal agents

Question 1

location of infections

Answer 1

cutaneous
subcutaneous
systemic infections

Question 2

Drugs for subcutaneous and systemic infections

Answer 2

Amphotericin B
Flucytosine (5-FC)
Triazoles
Echinocandins

Question 3

Drugs for cutaneous

Answer 3

Terbinafine
Griseofulvin
Nystatin
Imidazoles

Question 4

Imidazoles for fungal infections

Answer 4

ketoconazole

Clotrimazole

Question 5

Amphotericin B

Answer 5

fungicide or static depending on concentration and organism

MOA: binds to ergosterol and alters the membrane permeability

Pharmacokinetics:
Good distribution, does not enter CNS
Plasma half-life: 15 days
Lipid formulation has better effect and smaller toxicity
Administration: parenterally (IV microcolloid infusion or liposome packed) | intrathecally for candida meningitis | larger amounts can be given in lipid formulation

Spectrum: broad
Candida spp. Cr. Neoformans, aspergillus, dimorphs
Some protozoans (Leishmania and Trypanosoma)

Low TI
Adverse effects: Infusion related toxicity – fever, chills, anemia, thrombophlebitis | Kidney damage, hypotension

Question 6

Flucytosine (5-FC)

Answer 6

Fungistatic
MOA: transformed to 5-FU, incorporated into the RNA, inhibits the protein synthesis, synergism with amphotericin B

Pharmacokinetics: 
good absorption
 good distribution also in CSF
Administration: oral and parenteral
Excretion: Kidney (glomerular filtration) 

Spectrum: candida sp., Cryptococcus, aspergillus

Clinical use:
Urinary tract candidiasis In combination with amphotericin B or maybe itraconazole
pulmonary aspergillosis, Cryptococcus meningitis

Adverse effects: GI (severe enterocolitis may occur), liver impairment, bone marrow toxicity

Question 7

Triazoles

Answer 7

Itraconazole
Fluconazole
Voriconazole
Posaconazole

Question 8

Itraconazole
Fluconazole
Voriconazole
Posaconazole

Answer 8

MOA: Inhibition of ergosterol synthesis (cytochrome P450 enzyme)
Disrupts membrane structure and function of growing fungi

Spectrum: all fungi except aspergillus
!!! Voriconazole also against aspergillus and highly effective against Candida spp.

Inhibition of CYP3A4
Adverse effects: GI, liver impairment, antiandrogen effect

Question 9

Itraconazole

Answer 9

administration: oral
accumulation in nail

treats blastomycosis, paracoccidioidomycosis, Histoplasmosis

Adverse effects: liver impairment, antiandrogen effect
Hypokalemia, hepatotoxicity

Question 10

Fluconazole

Answer 10

hydrophilic

administration: oral, parenteral

distributes in CSF
elimination via kidney

DOC for cryptococcus neoformans after induction therapy

Question 11

Posaconazole

Answer 11

broadest spectrum of the Triazoles

Question 12

Voriconazole

Answer 12

also against aspergillus and highly effective against Candida spp.
Administration: oral, parenteral

Question 13

Echinocandins

Answer 13

caspofungin
micafungin
anidulafungin

Question 14

caspofungin
micafungin
anidulafungin

Answer 14

Echinocandins

MAO: interfere with the synthesis of the cell wall by inhibiting the synthesis of β(1,3)-D-glucan, leading to lysis and cell death (Inhibitors of polysaccharide synthesis)

Indications: Aspergillus, Candida sepsis, if poly resistant (minimal activity against other fungi)

Administration: IV

Adverse effects: well tolerated rash, fever, phlebitis at the infusion site.

Question 15

Caspofungin

Answer 15

first line in invasive candidiasis 2nd line for invasive aspergillosis

Question 16

Terbinafine

Answer 16

Mechanism: inhibition of squalene epoxidase inhibitor

DOC: dermatophyte onychomycosis (nail infection) | 3 months therapy
Oral form: tinea capitis
Topical form: tinea pedis, tinea corporis, tinea cruris | 1 week therapy

Kinetics: accumulation in nail, skin, breast milk and adipose tissue
excreted via urine

Adverse effects: GI symptoms (diarrhea, dyspepsia, nausea), headache, rash, rarely hepatitis, pregnancy is contraindication

Question 17

Griseofulvin

Answer 17

MOA: disruption of mitotic spindle (inhibition of fungal mitosis)
Fungistatic

Onychomycosis treatment of 6-12 month (duration according to replacement of skin tissue)
Treats also dermatophytosis of the scalp

Many side effects: liver damage, bone marrow damage, GI, photosensitivity, psychic problems, enzyme inducer, teratogenic

Question 18

Nystatin

Answer 18

Poleyn antifungal

Pharmacokinetics: no absorption from GI, local effect

Adverse effects: GI symptoms
“Swish and swallow”

Clinical use: mouth and cutaneous candida infection, Cryptococcus, histoplasma, blastomyces

Question 19

ketoconazole

Clotrimazole

Answer 19

MOA: Inhibition of ergosterol synthesis (cytochrome P450 enzyme)
Disrupts membrane structure and function of growing fungi
Wide range of activity

Spectrum: epidermophyton, Microsporum, trichophyton, candida, malassezia

Used for: tinea pedis, tinea corporis, tinea cruris | Oropharyngeal and vuvovaginal candidiasis