Antifungal Agents

Question 1

Fungi

Answer 1

Eukaryotic organisms that live as saprophytes or parasites. Resistant to ABX.
Termed Mycoses

Question 2

Types of Fungi

Answer 2

Superficial- skin, nail/hair, mucous membranes

Systemic- deep tissues, organs

Question 3

3 Groups of fungi that cause disease

Answer 3

Molds
True yeast
Yeast-like fungi

Question 4

Fungal pathogenicity results from

Answer 4

Mycotoxin production
Allergenicity/inflammatory reactions
Tissue invasion
Opportunistic fungal infections are important causes of disease in immunosuppressed

Question 5

Route selection for superficial and cutaneous infections

Answer 5

Selection of anti fungal therapy should be based on extent and type of infection
Superficial and cutaneous- usually topical
Follicular, nail, or widespread- systemically

Question 6

Vehicle selection

Answer 6

Ranking the drying effect of formulations
gel>lotion/solutions/cream/ointment
Powders are used only as adjuncts

Question 7

Systemic fungal infections

Answer 7

Tx depends on stage and severity
Choices revolve around the same drugs for all systemic fungal infections
Risk factors include- immunosuppression (HIV, CA chemo, or steroids), diabetes, TPN

Question 8

Antifungal Drugs

Answer 8

Polyene antibiotics
Imidazole antifungals
Triazole antifungals
Other antifungal agents 
Tx can last weeks to months and is more effective on the skin than the nails.

Question 9

Amphortericin B

Answer 9

Polyene ABX
Naturally occuring polyene macrolide antibiotic produced by streptomyces nodosus
MOA- Bind to ergosterol in the fungal cell membrane and form pore-> leak “-cidal”
Selective toxicity
Resistance- infrequent due to decreased ergosterols in membrane

Question 10

Nystatin

Answer 10

Polyene ABX
MOA- Bind to ergosterol in the fungal cell membrane and form pore-> leak “-cidal”
Selective toxicity
Active transport mechanism

Question 11

Amphortericin- pharmacokinetics

Answer 11

ROA- IV

Liposomal preps less renal and infusion toxicity

Question 12

Amphortericin indications and ADRS

Answer 12

Broad specturm anti-fungal used in potentially fatal systemic infections
-Candida albicans, histoplamsa capsulatum, cyrptococcus neoformans, coccidoices immites, blastomyces dermatitides, aspergillis
ADRs- HYPOTENSiON, anemia, nephrotoxocity, thrombophlebitis, fever/chills, allergic reactions

Question 13

Nystatin-pharmacokinetics

Answer 13

Topically as a cream
Vaginal troches
Suspension deliver drugs to oral mucosa

Question 14

Nystatin- indications and ADRS

Answer 14

Used to supress candidiasis on the sin and mucous membranes (oral&vaginal)
ADRs- N/V/D

Question 15

Flucytosine (Ancobon)

Answer 15

Polyene ABX
MOA- inhibits synthesis of fungal pyrimidines
ROA- PO
Indications- in combination w/ amphoB to treat systemic candiasis and cryptococcuss meningitis
ADRs- N/V/D, rare hepatotoxicity and seen more often is thrombocytopenia, neutropenia, bone marrow suppression

Question 16

Griseofulvin (Fulvicin)

Answer 16

Polyene ABX
MOA- binds to fungal microtubules disrupting mitotic spindles “-static”
Indications- DOC in kinds for wide spread dermatophyte or intractable dermatophyte infection where topical agents have failed. No longer for dermatophyte infection of nails
ADRs- fever, HA, mental confusion, rashes, GI disturbances.

Question 17

Griseofulvin (Fulvicin)- drug interactions

Answer 17

P450 inducer- barbiturates, OCP, warfarin
High fat meals increase absorption
Potentiates intoxicating effects of ETOH

Question 18

Ketoconazole (nizoral)- MOA

Answer 18

Azoles Imidazoles
MOA- broad spectrum: histoplasma, blastomyces, candida, coccidioides, NO ASPERGILLUS
Predominately fungistatic but can be -cidal depending on dose
Inhbits C-14-alpha-demethylase (P450 enzyme) disruptong the membrane
Also inhibits human steroid synthesis leading to decreased testosterone and cortisol production.

Question 19

Ketoconazole (nizarol)- Pharmacokinetics and ADR

Answer 19

PO-requires gastric acid for dissolution
Penetration into tissues limites, effective in tx of histoplasmosis in lung, bone, skin, soft tissue
Doesn’t enter CNS
ADRs- N/V, anorexia, endocrine effects such as gynecomastia, impotence, irreg menses, teratogenic due to endocrine effects

Question 20

Ketoconazole (nizarol)- Drug interactions and resistance

Answer 20

P450 INHIBITOR
Resistance- mutation of p450 enzyme leasts to decreased azole binding
Ability to pump azole out of the cell.

Question 21

Azoles Imidazoles

Answer 21

Clotrimazole (Lortimin, mycelex)
Miconazole (Monostat, desenex)
Terconazole (terazol)
Butoconazole (Femstat3)
Topical only; severe toxicity when used IV
MOA and spectrum same as ketoconazole
Topical use w/ contact dermititis, vulvar irritation, edema
TOPICAL MICONAZOLE IS A POTENT INHIBITOR OF WARFARIN METABOLISM

Question 22

Fluconazole (diflucan)- MOA

Answer 22

Azoles Triazoles
Inhibits synthesis of fungal membrane ergosterol
Lacks endocrine side effects
Penetrates CSF of normal and inflammed meninges

Question 23

Fluconozole (diflucan)- uses, ROA and ADRs

Answer 23

DOC- cryptococcuss neoformans, candidemia and coccidioidomycosis, effective against all forms of mucocutaneous candidiasis; used prophylactically in immunocompromised pts
ROA- Oral or IV
ADRs- N/V and rash

Question 24

Fluconazole (diflucan)- drug interactions

Answer 24

Moderate inhibitor of CYP3A4 (cyclosporin, lovastatin) and strong inhibitor of CYP2C9
Tetratogenic

Question 25

Itraconazole (Sporanox)

Answer 25

Azoles triazoles
MOA- inhibits synthesis of fungal membrane ergosterol lacks endocrine side effects; -static
DOC- blastomycosis, aspergillis, sporotrichosis, paracoccidiodomycosis, histoplasmosis

Question 26

Itraconazole (sporanoz)- pharmacokinetics and ADRs

Answer 26

PO- requires acid for dissolution
Extensively protein bound and distributes throughout most tissues including bone and adipose, but not CSF
Biologically an active metabolite
P450 INHIBITOR
Avoid in pregnancy
ADRs- N/V, rash, hypokalemia, HTN, edema, HA

Question 27

Itraconazole (sporanox)- contraindications

Answer 27

Strong inhibitor and substrate of CYP34A, contraindicated w/ lovastatin, simvastatin, midazolam, triazolam. May decrease OCP effectiveness, and increased digoxin levels

Question 28

Voriconazole (vfend)

Answer 28

Azole triazoles
PO or IV
Invasive aspergillosis and serious infections caused by scedosproium apiospermum and fusarium species
Penetrates tissues and CSF
ADRs- similar to other azoles; transient visual disturbance occurring shortly after dose

Question 29

Voriconazole (vfend)- Contraindictations

Answer 29

Inhibitor of CYP2C18, 2C9, 3A4. Contraindicated in patients taking rifampin, phenobarital, carbamasepine. Dose adjustments may be required w/ statins, benzodiazepines, and warfarin

Question 30

Posaconazole

Answer 30

Azole triazoles (new antigungal)
Only available as oral suspension and must be taken with high fat meal for adequate absorption
Spectrum similar to itraconazole, w/ additional effect on Zygomycetes such as mucor
More effective than other azoles in treating fungal infections in immunosuppressed patients (myelogenous leukemia, stem cell transplantation, refractory esophageal candidiasis)
Inhibits CYP3A4

Question 31

Terbinafine (Lamisil)

Answer 31

Allylamines
MOA- prevents ergosterol synthesis by inhibiting the enzyme squalene oxidase; -cidal
PK- lipophillic- penetrates superficial tissues including the nails
Administered orally- fingernail and toenail regimens differ, 40% bioavailability due to 1st pass metabolism, therapy is 3 months.

Question 32

Terbinafine (lamisil)- indications and ADRS

Answer 32

Active against dermatophytes and candida albicans
ADR- mild- HA, N/Dm rash, taste and visual disturbance
Rare but serious effects- cholestatic jaundice, blood dyscrasias, steven-johnson syndrome
Baseline LFTs and CBC (repeat q 4-6wks)

Question 33

Onychomycosis (nail infection) treatments

Answer 33

Terbinafine- 1st line agent (not candida)
Itraconazole- alternative 1st line therapy (preferred for candida infections)
These drugs have REPLACED grseofulvin and ketoconazole for this type of infection

Question 34

Caspofungin (Cancidas)

Answer 34

Echinocandins
2nd line therapy for those who failed amphoB or itraconazole (expensive)
Interferes w/ synthesis of fungal wall
Limited to aspergillus and candida species
ADRs- fever, rash, nausea, phlebitis, and flushing rxn.

Question 35

Micafungin (Mycamine)

Answer 35

Echinocandins
Esophageal candidas
Prophylaxis of invasive candida infections in pts undergoing hematopietic stem cell transplantation
ADRs- fever, rash, nausea, phlebitis, and flushing rxn.