Anti-Fungal Agents

Question 1

What has the broadest spectrum of all anti-fungal agents?

Answer 1

Amphotericin B

Question 2

Amphotericin B ROA

Answer 2

IV - not orally absorbed

Question 3

What is Amphotericin B standard of care for?

Answer 3

Life threatening fungal infections

Question 4

What are the problems with Amphotericin B?

Answer 4

It has significant adverse side effects

Question 5

Amphotericin B MOA

Answer 5

• Ampho B binds to ergosterol in fungal membrane

- Forms pore in the membrane thereby increasing membrane permeability

Question 6

How is amphotericin B specific for fungi?

Answer 6

Binds to ergosterol but only weakly to cholesterol so it does not affect host cells as much

Question 7

What is the only fungi amphotericin B is not effective against?

Answer 7

Pseudallescheria boydii

Question 8

What is amphotericin B resistance associated with?

Answer 8

Decreased ergosterol in the cell membrane

Question 9

What is the typical regimen of therapy for amphotericin B?

Answer 9

Used as an initial induction therapy (typically 4 weeks) to reduce fungal burden, then replaced by newer, less toxic AZOLE drugs for consolidation therapy and prevention of relapse

Question 10

What is the treatment of choice for Zygomycosis/mucormycosis?

Answer 10

Amphotericin B

Question 11

What is the only anti-fungal agent approved for pregnant and breastfeeding women?

Answer 11

Amphotericin B

Question 12

Amphotericin B SE

Answer 12

• Fever, chills, muscle spasms, vomiting, headache and hypotension
• Nephrotoxicity
• Hepatotoxicity
• Anemia

Question 13

Flucytosine Pharmokinetics

Answer 13

• Good oral bioavailability

- Good penetration into the CSF

Question 14

What does the CSF penetration of flucytosine make it useful in treating?

Answer 14

Cryptococcus meningitis

Question 15

Is dosage adjustment of Flucytosine required in renal failure?

Answer 15

Dosage adjustment required in presence of renal insufficiency

Question 16

Flucytosine MOA

Answer 16

Taken up via cytosine permease and converted by fungal-specific cytosine deaminase to 5-FU analogs that inhibit thymidylate synthase (DNA synthesis) and RNA synthesis

Question 17

Spectrum of Action of Flucytosine

Answer 17

• Cryptococcus neoformans
• Candida sp
• Agents of chromoblastomycosis

Question 18

Why is the use of flucytosine restricted?

Answer 18

Acquired resistance is very high

Question 19

How does amphotericin B interact with flucytosine?

Answer 19

Ampho B enhances fungal cell uptake of flucytosine as it generates pores in the fungal cell wall

Question 20

Flucytosine SE

Answer 20

• GI effects
• Bone marrow toxicity
• Anemia
• Teratogenic

Question 21

What are the 2 groups of -azole drugs and what are the drugs in each class?

Answer 21

Imidazoles
- Ketoconazole (prototype)

Triazoles

• Fluconazole
• Itraconazole
• Voriconazole
• Posaconazole

Question 22

What is the general spectrum of activity of all of the -azoles?

Answer 22

All have some activity against Candida and Cryptococcus

Question 23

What is the order of the azoles from narrowest in spectrum to broadest spectrum?

Answer 23

Fluconazole - Itraconazole - Voriconazole - Posaconazole

Question 24

Why do -azoles have a large potential for drug interactions?

Answer 24

They are all major inhibitors of CYP450

Question 25

-azole MOA

Answer 25

Inhibit 14α􏰇-sterol demethylase involved in the biosynthesis of ergosterol, an essential component of fungal membranes

Question 26

-azole SE

Answer 26

* GI Distress * Hepatotoxicity- requires hepatic enzyme monitoring * Can cause fetal abnormalities

Question 27

Which -azoles are related to the most drug interactions?

Answer 27

Most drug interactions are associated with Itraconazole and Voriconazole

Question 28

Itraconazole and Voriconazole Contraindications

Answer 28

Itraconazole and Voriconazole should NEVER be given to a patient taking STATINs due to increased risk of developing fatal Rhabdomyolysis

Question 29

Ketoconazole Pharmokinetics

Answer 29

- Oral ketaconazole requires acidic environment for absorption - Poor penetration into CSF and urine

Question 30

Fluconazole Pharmokinetics

Answer 30

Good oral bioavailability and Excellent penetration into the CSF

Question 31

What drug has the fewest drug interactions of all the -azoles?

Answer 31

Fluconazole

Question 32

Fluconazole SE

Answer 32

- Nausea, headache, skin rash and GI | - Alopecia (reversible) associated with long duration/high dose therapy

Question 33

Why is fluconazole useful for fungal bladder infections?

Answer 33

80% of drug eliminated unchanged in the urine

Question 34

Itraconazole Pharmokinetics

Answer 34

Poor penetration of CSF, urine and eye

Question 35

Itraconazole SE

Answer 35

- Triad of Hypertension, Hypokalemia and Peripheral Edema | - Can cause CHF in patients with ventricular dysfunction

Question 36

Voriconazole Pharmokinetics

Answer 36

Well absorbed, broadly distributed into tissues including CSF - bioavailability is unpredictable and affected by genetic polymorphisms

Question 37

What is unique about the metabolism of voriconazole?

Answer 37

Non-linear metabolism - 50% increase in dose =􏰆 150% increase in serum concentration

Question 38

What is the treatment of choice for invasive Aspergillus?

Answer 38

Voriconazole

Question 39

Voriconazole SE

Answer 39

- Periostitis - Transient vision changes - Photosensitivity/Rash- rarely Stevens Johnson syndrome ONLY with very high doses - Visual/Auditory hallucinations - Seizures

Question 40

Posaconazole Pharmokinetics

Answer 40

Readily distributes to tissues, but POOR penetration of CSF and URINE

Question 41

What is the only azole effective VS Zygomycosis/Murcormycosis?

Answer 41

Posaconazole

Question 42

What are the Echinocandins?

Answer 42

Caspofungin Micafungin Anidulafungin

Question 43

Echinocandin Pharmokinetics

Answer 43

Poor penetration of CSF

Question 44

Echinocandin SE

Answer 44

Well tolerated- few adverse effects - Histamine-like effect (skin itching)- associated with rapid infusion - Embryotoxic- NOT TO BE USED IN PREGNANCY

Question 45

Echinocandin MOA

Answer 45

Echinocandins competitively inhibit 􏰃ß(1-3)-D-glucan synthase complex involved in the biosynthesis of the principal building block of the fungal cell wall - impairs structural integrity of fungal cell wall - increases osmotic instability leading to cell death

Question 46

What do echinocandins lack activity against?

Answer 46

Cryptococcus or dimorphic fungi

Question 47

Griseofulvin Clinical Use

Answer 47

Only clinical use is for the treatment of mycotic infections of the skin, nail and hair due to dermatophytes: Microsporum, Epidermophyton & Trichophyton

Question 48

Griseofulvin MOA

Answer 48

The drug is fungistatic and binds to fungal microtubules, preventing the formation of the mitotic spindle and inhibiting fungal mitosis

Question 49

Terbinafine Clinical Use

Answer 49

* Activity is limited to dermatophytes and Candida albicans | * Used in the treatment of tinea captis, tinea corpis, tinea cruis, tinea pedis and onchomycosis

Question 50

Terbinafine MOA

Answer 50

Inhibition of fungal SQUALENE EPOXIDASE in membrane synthesis which leads to a build up of squalene which is toxic to the fungal cells

Question 51

Nystatin MOA

Answer 51

Binds to ergosterol and forms pores in the fungal membrane - like ampho B

Question 52

Nystatin ROA

Answer 52

Too toxic for IV - only in gels, creams and ointments

Question 53

What is nystatin not active against?

Answer 53

Not active against dermatophytes

Question 54

opical Azoles: Clotrimazole, Miconazole and Terconazole Clinical Uses

Answer 54

Oral and Vulvovaginal candidiasis | Dermatophyte infections

Question 55

Topical Allylamines: Terbinafine and Naftifine and Benzylamines: Butenafine Clinical Uses

Answer 55

Candida albicans and dermatophytes | - Used in the treatment of tinea cruris, tinea corporis and tinea pedis