Antifungals

Question 1

Five main antifungal drug classes/drugs:

Answer 1

1) Polyenes
2) Azoles
3) Pneumocandins (& echinocandins)
(4) Pyrimidines)
5) Drugs used to treat dermatophytosis

Question 2

polyenes: an important drug in this category, and some characteristics

Answer 2

1) Polyenes
* E.g., amphotericin B
* Broad spectrum, fungicidal
* High systemic toxicity

Question 3

azoles: an important drug in this category, and some characteristics

Answer 3

• E.g., itraconazole
• Broad spectrum, fungistatic
• Very low toxicity

Question 4

pneumocandins: an important drug in this category, and some characteristics

Answer 4

• Newest AF drugs, low toxicity, replacing polyenes for systemic therapy
• E.g., caspofungin

Question 5

important drug used to treat dermatophytosis

Answer 5

Terbinafine

Question 6

difference between bacterial and fungal cell and consequence

Answer 6

Unlike bacteria, fungi are eukaryotic
>harder to attack without affecting host

Question 7

main targets of antifungal drugs, generally

Answer 7

Plasma membrane
>Most systemic drugs (polyenes, azoles)

Cell wall
>(pneumocandins)

Protein synthesis, Nucleic acid synthesis
>(Flucytosine)

Question 8

specific component of fungal plasma membrane that is the target of many antifungals

Answer 8

Plasma membrane contains ergosterol instead of cholesterol
> target of many antifungals

Question 9

plyenes mechanism of action and toxicity

Answer 9

Polyenes bind ergosterol in fungal membrane
> inserted into membrane
> several molecules come together to form a pore
> pores cause fungal cell to lyse (fungicidal)

Unfortunately, it also binds cholesterol to some extent in mammalian cells somewhat > toxic to host

Question 10

what is Amphotericin B?

Answer 10

A polyene macrolide antifungal

Question 11

pharmacokinetics of Amphotericin B; absorption, distribution

Answer 11

Conventional amphotericin B is usually formulated with bile salts to improve solubility, however can cause adverse effects

Poor oral absorption; usually given IV
Distributes to extracellular fluid; poorly into CNS

Question 12

pharmacokinetics of Amphotericin B; elimination

Answer 12

Most metabolized in liver
> bile; smaller amount excreted in urine

Long half-life: ~ 26 h in dogs; drug continues to be excreted for weeks after discontinuation of therapy

Question 13

spectrum of Amphotericin B

Answer 13

Broad (greater than the azoles)
* Many serious systemic mycotic infections

Question 14

clinical use of amphotericin B

Answer 14

Systemically, main use is in dogs & cats with life-threatening systemic mycoses, esp. in immunocompromised patients due to the fungicidal nature of the drug

Ampho B is often administered once followed by longer follow-up therapy with azole

Systemic use is sporadic in equine medicine, rare/absent in food animals

Question 15

route of administration of amphotericin in most species

Answer 15

Topical administration in most species

Question 16

Amphotericin B adverse effects and how to minimize

Answer 16

The most toxic antimicrobial drug in clinical use

Main adverse effect is dose-dependent nephrotoxicity seen primarily with bile salt formulations

IV admin should be slow (4-6 h)

Lipid-complex formulations are much safer

Question 17

The first relatively safe class of antifungal drugs; now the most commonly used for systemic antifungal therapy

Answer 17

Azoles

Question 18

Azoles spectrum and bioavailability

Answer 18

Broad spectrum; fungistatic

Good oral bioavailability

Question 19

which types of azoles are worse for systemic use and more toxic? which are better? which are good for topical?

Answer 19

For systemic use, older imidazoles (e.g., ketoconazole) are usually less effective and are more toxic than newer triazoles (e.g., itraconazole)

For topical use, imidazoles & triazoles are
often interchangeable (good efficacy, low toxicity)

Question 20

Azoles mechanism of action

Answer 20

Triazoles inhibit fungal P450 enzymes involved in ergosterol formation
>generally fungistatic effect

Azoles inhibit mammalian hepatic P450 enzymes
> inhibits metabolism of many concurrently administered drugs

Question 21

difference in safety profile between imidazoles and triazoles

Answer 21

Imidazoles: endocrine adverse effects are common with systemic therapy

Triazoles: generally very safe

Question 22

types of azoles?

Answer 22

imidazoles and triazoles

Question 23

what is ketoconazole? what is it used for?

Answer 23

Systemic imidazole
* The first azole to be marketed
* No longer used as an antifungal (eclipsed by the triazoles)
because it inhibits mammalian sterol synthesis

• Sometimes used in the management of hyperadrenocorticism because of its ability to inhibit cortisol synthesis (a use unrelated to its antifungal properties)

Question 24

what is ketoconazole? what is it used for?

Answer 24

Systemic imidazole
* The first azole to be marketed
* No longer used as an antifungal (eclipsed by the triazoles)
because it inhibits mammalian sterol synthesis

• Sometimes used in the management of hyperadrenocorticism because of its ability to inhibit cortisol synthesis (a use unrelated to its antifungal properties)

Question 25

Some topical imidazoles? why are they not used systemically?

Answer 25

Miconazole Clotrimazole Enilconazole (Drugs too toxic for systemic use)

Question 26

what type of drug is itraconazole? what is its spectrum, absorption, safety?

Answer 26

Fairly broad spectrum triazole >used in cats, dogs Good oral absorption No adverse effects on mammalian steroid synthesis Contraindicated in pregnancy > teratogenic effects

Question 27

what are echinocandins? what is the main example? what is the mechanism?

Answer 27

A new class of antifungal drugs Caspofungin is the main example * Mechanism: Inhibits fungal cell wall synthesis

Question 28

what are the uses of echinocandins?

Answer 28

* Fungistatic activity against Aspergillus spp., fungicidal activity against most Candida spp. * In humans, all agents are well tolerated, with similar adverse effect profiles and few drug-drug interactions * No animal data; experimental; expensive spectrum is narrower than polyenes

Question 29

what is the mechanism of terbafine?

Answer 29

inhibits ergosterol synthesis in virtually all dermatophytes (and several other types of fungi) * Toxic metabolites accumulate > fungicidal

Question 30

uses of terbinafine

Answer 30

fungicidal * Originally more effective than itraconazole or griseofulvin for dermatophytosis, but resistance is a moving target and it depends on the strain * Works synergistically with azoles - Novartis * Cats: Administered topically & orally; clipping may be important Dogs: Topical treatment alone is acceptable for localized infections but generalized infections respond better to topical + oral *** In severe cases, combination of oral & topical treatment of clipped animals gives fastest resolution (whether using terbinafine or azoles or a combination of drugs)** * Distributes to skin, nails, fat (& milk) * Available over-the-counter

Question 31

time of treatment for terbafine

Answer 31

Enters newly forming keratin > therapy typically requires 1-3 months for mycological cure (much longer for nails)

Question 32

main adverse effects of terbinafine

Answer 32

* Low incidence of adverse effects in dogs & cats > well tolerated even for prolonged therapy (60 days) * May see GI upset; nausea & vomiting may indicate hepatic injury; rare but severe skin problems * Inhibits some hepatic P450 enzymes > consider in animals receiving other drugs metabolized in the liver

Question 33

Tolnaftate is useful against?

Answer 33

Effective against dermatophytes

Question 34

how can we treat candida albicans?

Answer 34

* Mucocutaneous infections in many species * Usually secondary to prolonged antibacterial treatment or immunosuppression Treatment: -Manage predisposing factors -Depending on location, severity: >Topical azole or polyene if lesions accessible >Systemic azole or polyene +/- other

Question 35

how can we treat Aspergillus fumigatus?

Answer 35

* Mucous membranes in dogs * Air sacs in poultry * Guttural pouch in horses * Mastitis & abortion in cattle Treatment: -Usually preventable via management -Depending on location, severity: >Topical azole or polyene if lesions accessible >Polyene or azole +/- other

Question 36

how can we treat Blastomyces dermatitidis?

Answer 36

* Disseminated disease often starting in lungs, esp. in dogs Treatment: -May require combined amphotericin B + azole -Often requires prolonged treatment if established -Often combine with anti- inflammatory therapy for tx of fungal pneumonia, otherwise dead fungal cells trigger pulmonary inflammatory reaction that can be fatal