Lecture 7 antifungals

Question 1

Which people are most at risk of fungal infections?

Answer 1

Immunosuppressed, people on antimicrobial therapy, diabetes and very young or very old people.

Question 2

Why are many anti fungal drugs toxic?

Answer 2

Fungi have similar metabolic, protein synthesis and mitosis pathways to human cells, and so the development of selective drugs is very difficult. many antifungals therefore affect human cells as well.

Question 3

What are the three classes of mycoses?

Answer 3

Cutaneous, subcutaneous and systemic.

Question 4

Describe cutaneous mycoses.

Answer 4

Restricted to the keratinised layers of the skin, hair and nails. Caused by dermatophytes, including microsporum, trichophyton and epidermophyton fungi.
Resulting diseases include ringworm and tinea.
Dermatophytes obtain their nutrients from keratinised material.

Question 5

Describe subcutaneous mycoses.

Answer 5

Involve the dermis, subcutaneous tissues, muscle and fascia. Chronic infections initiated by piercing trauma to the skin. Difficult to treat and may require surgical intervention, e.g. debridement.

Question 6

Describe systemic mycoses due to primary pathogens.

Answer 6

Originate primarily in the lungs and may spread to many organ systems. Organisms that cause systemic mycoses are inherently virulent.

Question 7

Describe systemic mycoses due to opportunistic pathogens.

Answer 7

Infection of patients with immune deficiencies. Eg Candidiasis, Cryptococcosis, Aspergillosis and Zygomycosis.
Pneumocystis jiroveci pneumonia is caused by a yeast-like fungus.

Question 8

Describe the MOA and clinical applications of griseofulvin.

Answer 8

Disrupts fungal cell microtubule function. May produce defective DNA preventing cell replication (inhibits mitosis).
Treatment of choice for dermatophyte infections of scalp and hair (tinea capitis), and also tinea infection of skin, nails, feet and groin.

Question 9

Describe the limitations of use of griseofulvin, and its common and serious adverse effects.

Answer 9

Use of oral griseofulvin is limited due to availability of other topical antifungals, and other antifungals with fewer adverse effects.
Common effects include headache, lethargy, vertigo and increased decal protoporphin levels.
Serious effects include hepatotoxicity, neutropenia, monocytosis, serum sickness.

Question 10

What are the contraindications and precautions of griseofulvin?

Answer 10

CI: Pregnancy, porphyria and hepatic failure, lupus erythematosis.
Precautions: Avoid in prey and breast feeding. May affect sperm (men should not father a child during and 6 months after treatment). Women should use additional contraception while taking, and 1 month after stopping griseofulvin.

Question 11

What are the therapeutic considerations for griseofulvin?

Answer 11

Concurent administration with barbiturates decreases GI absorption of griseofulvin and induces metabolism.
Griseofulvin induces hepatic P450 enzymes which may result in increased metabolism of warfarin, and reduced efficacy of low oestrogen oral contraceptives.

Question 12

What are the counselling points for griseofulvin?

Answer 12

Take with food or milk to increase absorption.
May cause dizziness.
Very occasionally results in increased heart rate and skin flushing if combined with alcohol.
Increases sensitivity to sunlight.
Reduces effectiveness of oral contraceptive.
For nail infections, the treatment needs to be taken until the infected nail has grown out.

Question 13

What are some practice points for griseofulvin?

Answer 13

Treatment of choice for tine capitis. Terbinafine or itraconazole are preferred for nail infections.
Generally well tolerated.
Narrow spectrum of activity and largely confined to dermatophytes.
monitor complete blood count during prolonged treatment.

Question 14

Describe the mechanism of action and indications for use of terbinafine.

Answer 14

Terbinafine is an allylamine, and prevents ergosterol synthesis by inhibiting squalling oxidase, resulting in squalling accumulation and causing membrane destruction and cell death (fungicidal).
Indicated for use for dermatophyte infection of the nails, skin, groin and feet where topical treatment is ineffective or inappropriate.

Question 15

Describe the kinetics of terbinafine.

Answer 15

Well absorbed. Is concentrated in the dermis, epidermis and adipose tissue. Diffuses from the nail bed, penetrating distal nails within 4 weeks. Metabolised in liver, and inactive metabolites excreted in urine.

Question 16

What is a precaution of terbinafine use, common adverse effects and serious adverse effects?

Answer 16

May worsen psoriasis.
GI disturbance is a common adverse effect. Serious adverse effects include hepatotoxicity, Stevens-Johnson syndrome, neutropenia.

Question 17

What is a therapeutic consideration of terbinafine?

Answer 17

CYP2D6 inhibitor. Has fewer interactions than azole antifungals. Plasma levels are increased by cimetidine and reduced by rifampicin.

Question 18

Counselling points for terbinafine?

Answer 18

Tell doctor if you are unusually tired, nauseous or are not eating, or if you notice dark urine or pale stools, or yellowing of the whites of your eyes.
For nail infection, the nail needs to grow out before it looks completely normal.

Question 19

What are the practice points for terbinafine?

Answer 19

Treatment of choice for dermatophyte onychomycosis.
May be used for other forms of tine where griseofulvin is ineffective (treat for 4-6 weeks).
Obtain liver function tests at baseline, monitor these and blood count if treating for more than 6 weeks.
Stop treatment if hepatotoxicity occurs or a rash worsens.

Question 20

Describe amorolfine, including class, MOA, indications.

Answer 20

A morpholine antifungal for skin infections. Interferes with the synthesis of sterols essential for function of fungal cell membranes. Indicated for use in onychomycoses.

Question 21

Describe counselling points for amorolfine.

Answer 21

Before first application, thoroughly file down then clean and degrease the affected areas of nail using cleaning pad provided. Apply to entire surface of the affected nails and allow to dry.

Question 22

Describe the MOA, drug interactions of azoles. Give examples.

Answer 22

Includes imidazoles and triazoles. Inhibit ergosterol synthesis in fungal cell membrane (fungistatic).
Inhibit several CYP enzymes and inhibit the metabolism of most hepatically metabolised drugs.

Question 23

Describe imidazoles (including dosage form) and give examples.

Answer 23

Broad spectrum, e.g. clotrimazole (topical), econazole (topical), miconazole (topical) and Ketoconazole (local and systemic infections, well absorbed orally.
All are used topically to treat dermatophyte and candida albicans infections.
Ketoconazole blocks the synthesis of hydrocortisone and testosterone. May cause hepatic necrosis.

Question 24

Describe triazoles and give examples.

Answer 24

Wider spectrum than imidazoles: inhibit ergosterol synthesis and have less adverse effects.
Fluconazole: Oral and IV admin. Wide range of superficial and systemic mycoses (not Aspergilus). Does not have the adverse effects of ketoconazole. Inhibits CYP2C9 and CYP3A4.
Itraconazole: Absorbed orally. effective against Aspergilus. Superficial dermatophyte or candidal infections. Decreases gastric acidity (treat with proton pump inhibitor but may impair absorption from capsule). Give with coke and monitor response.

Question 25

Describe Voriconazole and posaconazole.

Answer 25

Voriconazole: new broad spectrum drug for life-threatening infections. Causes altered visual perception, blurred vision, colour changes and photophobia. May select for infection with zygomycetes.
Posaconazole: serious infections where other antifungals have failed or are inappropriate. takes 10 days to reach steady state.

Question 26

Which triazole is preferred for fungal CNS infections?

Answer 26

Fluconazole

Question 27

Describe the class, indications and kinetics of nystatin.

Answer 27

Polyene anti fungal which is mainly active against candida species. Not active against dermatophytes.
Poorly absorbed from GI tract and not absorbed through skin or mucous membranes when applied topically. Useful for the topical treatment of Candida infections that are resistant to azoles, or where azoles cause irritation. Available as cream, tablets, capsules and oral drops.

Question 28

What is the MOA and indications of nystatin.

Answer 28

Binds to ergosterol in fungal cell membranes altering their permeability and allowing leakage of intracellular components. Indicated for use in oropharyngeal candidiasis, treatment and suppression of intestinal candidiasis, cutaneous and vulvovaginal candidiasis.

Question 29

Describe counselling for use of nyastatin in oropharyngeal candidiasis.

Answer 29

Best to use oral liquid after a meal or drink, rather than before. Swish around mouth for as long as comfortable before swallowing. Continue to use for about 2 days after symptoms resolve.

Question 30

Counselling for the use of nystatin in cutaneous candidiasis?

Answer 30

Have to use it regularly, and continue treatment for 2 weeks after symptoms have gone. Symptoms generally improve within 24-72 hours. Avoid occlusive dressings because they provide conditions that favour growth of yeast and release of endotoxin.

Question 31

Describe the adverse effects and counselling points of the use of vaginal nystatin for vulvovaginal candidiasis.

Answer 31

Even on prolonged administration, nystatin is virtually nontoxic, nonsensitizing and well tolerated by all age groups.
May damage contraceptive diaphragms and condoms. Do not use these medicines during treatment.

Question 32

Which anti fungal remains the treatment of choice for most serious systemic fungal infections? What is its MOA?

Answer 32

Amphotericin: Binds irreversibly to ergosterol in fungal cell membranes causing leakage and cell death. It is toxic, however a lipid formulation may be used with fewer toxic effects (costs much more).

Question 33

Describe the use of flucytosine, indications for use, and MOA.

Answer 33

IV or orally. Mainly used in combination with amphotericin against Cryptococcus neoformans (causes meningitis and pneumonia).
MOA: converted by cytosine deaminase to fluoracil in fungal cells. After phosphorylation, inhibits fungal DNA synthesis and is also incorporated into fungal RNA, affecting protein synthesis.

Question 34

Describe the use and MOA of echinocandins.

Answer 34

Used for systemic fungal infections in imunocompromised patients. Inhibit the synthesis of glucan in the cell wall via the enzyme 1,3-beta glucan synthase. This leads to lysis and cell death.

Question 35

Give examples of echinocandins, and describe drug interactions.

Answer 35

Anidulafungin and caspofungin. Drug interactions: Cyclosporin, which is a moderate CYP 3A4 inhibitor, increases caspofungin concentration and may increase risk of toxicity.
Rifampicin reduces caspofungin concentration.

Question 36

What is pentamidine used for, and how is it administered?

Answer 36

Pneumocystis pneumonia. Given by inhalation or IV.