Antifungals: Echinocandins, Griseofulvin, Terbinafine, Nystatin, Terbinafine

Question 1

The last drug in the category of systemic drugs for subcutaneous and systemic mycoses is an Echinocandins called Caspofungin. What are some features?

Answer 1

Newest class
Large cyclic peptide linked to a long chain fatty acid
Active against Candida and Aspergillus but not Cryptococcus Neoformans
Only available IV
Inhibits synthesis of B(1,3)-D-glucans in the fungal cell wall –results in disruption of the fungal cell wall and cell death.
Elevated liver enzymes when used in combo with cyclosporine (This combo should be avoided)

Question 2

What are the uses of Caspofungin?

Answer 2

Presumed fungal infections in febrile, neutropenic patients
Candidemia
Esophageal Candidiasis
Invasive aspergillosis in patients refractory to other therapies.

Question 3

Next group of drugs are those used for superficial mycoses. What are the superficial mycoses?

Answer 3

Superficial (cutaneous) mycoses are caused by:
–dermatophytes or candida
Dermatophytes are a group of Filamentous Fungi
Most cutaneous infections are Dermatophytic
—skin, hair or nails and classified based on area involved

Question 4

Cutaneous fungal infections are usually treated topically, but nail and hair infections, widespread dermatophytosis and chronic non responsive yeast infections are treated with what?

Answer 4

Oral anti-fungal drugs

Question 5

The first drug in the systemic drugs for superficial mycoses is Griseofulvin, what are some features?

Answer 5

Fungistatic drug
Only use tx of dermatophytosis
Absorption improved when given with fatty foods

Question 6

What is the MOA of Griseofulvin?

Answer 6

Enters susceptible cells by energy dependent process. Interacts with microtubules of the fungus to disrupt mitotic spindle and inhibit mitosis.
–accumulates in the infected keratin containing tissues making them unsuitable for the growth of the fungi. It must be administered for 2-6 weeks for skin and hair infections to allow the replacement of infected tissue by normal tissue.

Question 7

What are the uses and adverse effects of Griseofulvin?

Answer 7

Uses:
–indicated for severe dermatophytoses of the skin, hair and nails
–largely replaced by newer antifungal drugs like itraconazole and terbinafine
Adverse Effects:
–Induces liver P450 enzymes thus increasing the metabolism of a number of drugs, including warfarin

Question 8

The second drug in the systemic drugs for superficial mycoses is Terbinadine. What are some features and MOA?

Answer 8

Oral and Fungicidal
MOA:
–In the ergosterol synthesis pathway, squalene is converted to lanosterol by the action of the fungal enzyme squalene epoxidase. Terbinafine inhibits squalene epoxidase, thus preventing formation of lanosterol, which is the precursor of ergosterol.
–accumulation of toxic levels of squalene in the fungal cell making it fungicidal under most circumstances.

Question 9

What are the uses and adverse effects of Terbinadine?

Answer 9

Use:
–DOC: tx dermatophytoses and esp onychomycoses. It is better tolerated, requires shorter duration of therapy, and is more effective than either azoles or griseofulvin.
Adverse Effects:
–GI upsets, rash, HA
–does not affect P450 system and no significant drug interactions

Question 10

What is commonly used for oral treatment of dermatophytoses?

Answer 10

Ketoconazole
FLuconazole
Itraconazole

Question 11

Pulse or intermittent dosing with itraconazole is as effective in onychomycoses as continuous dosing because the drug persists in the nails for several months. What is the advantage of this dosing?

Answer 11

Include lower incidence of side effects and lower costs

Question 12

Next set of drugs are topical drugs for superficial mycoses. What are some general features?

Answer 12

Useful for many superficial fungal infections

• -those confined to stratum corneum, squamous mucosa, or cornea.
• -diseases: dermatophytosis (ringworm), candidiasis, tinea versicolor, piedra, tinea nigra and fungal keratitis
• -topical administration is usually not successful for mycoses of the nails (onychomycosis) and hair (tinea capitis)

Question 13

The first topical drug for superficial mycoses is Nystatin. What are some features?

Answer 13

Structurally similar to Amp B and has same MOA
Too toxic for IV admin
Used only for candidasis (cutaneous, vaginal or oral)
Not absorbed from the GI tract, skin or vagina (so little toxicity)

Question 14

Topical Amphotericin B is used for what?

Answer 14

Cutaneous candidiasis

Question 15

The topical azoles have a wide range of activity against dermatophytes and yeasts, including?

Answer 15

Candida Albicans

Pityrosporum Orbiculare

Question 16

What two azoles are most commonly used topically?

Answer 16

Clotrimazole and Miconazole

–often used for vulvovaginal candidiasis

Question 17

Topical Terbinafine is used for what?

Answer 17

Effective for Tinea cruris, pedis and corporis

–acts by inhibiting squalene epoxidase

Question 18

A note on Pneumocystis Jirovecii, is the organism responsible for Pneumocystis Pneumonia (PCP). What are some features?

Answer 18

Organism is now recognized to be a fungus; however, it responds to anti-protozoal drugs rather than to anti-fungals.
Common cause of pneumonia in immunocompromised patients. it is the most common opportunistic infection in HIV infected patients.

Question 19

What is the first line therapy for pneumocystosis?

Answer 19

Co-trimoxazole

–also standard chemoprophylactic drug for the prevention of P. jiroveci infection in immunocompromised individuals.

Question 20

What are alternative therapies?

Answer 20

Clindamycin + primaquine
Dapsone + trimethoprim 
Atovaquone 
Pentamidine 
--patients with moderate to severe disease should also be given corticosteroids: prednisone

Question 21

These last cards will be review cards. What is the primary therapy for Esophageal candidiasis, Urinary Candidiasis, Oropharyngeal Candidiasis, Vulvovaginal Candidiasis and Recurrent vulvovaginal candidiasis

Answer 21

Esophageal: IV or oral Fluconazole
Urinary: IV or oral Fluconazole
Oropharyngeal Candidiasis: Mild (topical clotrimazole or nystatin), Moderate to severe (oral fluconazole), AIDS ( oral fluconazole)
Vulvovaginal: Topical Azoles or Oral Fluconazole
Recurrent Vulvovaginal: Oral Fluconazole

Question 22

What is the primary treatment for Candidiemia, Cutaneous Candidiasis, Cryptococcosis, Invasive Aspergillosis, Mucormycosis, Fusariosis and Onychomycosis

Answer 22

Candidiemia: IV Fluconazole or IV Echinocandin
Cutaneous Candidiasis: Topical Amp B or Topical Azole or Topical Nystatin
Invasive Aspergillosis: IV and then oral Voriconazole
Mucormycosis: Amp b
Fusariosis:Amp B
Onychomycosis: Oral Terbinafine or Oral Itraconazole or Oral Fluconazole