Antifungals

Question 1

Types of Fungi

Answer 1

Yeast
Single cell, spherical or elliptical
Reproduce by asexually budding (blastoconidia) if bud stays attached
form pseudohyphae

Molds
Multicellular, form thread like filaments called hyphae
Mycelium is a mass of hyphae

Dimorphic fungi
Mold-cold, environment and Yeast-heat, in body

Question 2

fungal reproduction

Answer 2

Spore is produced from sexual reproduction and conidia from asexual reproduction. Both forms are stable in the environment. Hyphael filaments grow toward nutrients and can facilitate invasion.Haustoria are hyphae on parasitic fungi

Question 3

fungal weaknesses

Answer 3

Cell wall contains chitin and glucans

Plasma membrane contains ergosterol

Question 4

Polyenes: Amphotericin B and Nystatin

Answer 4

Mechanism: Binds ergosterol, creating holes in membrane allowing leakage of electrolytes. Fungicidal

Broad spectrum: Used for invasive systemic fungal infections in immunocompromised patients. Active against yeast and molds.

Distribution: Small fraction of drug is excreted and has a long tissue half life. Liposomal form can cross blood brain barrier.

Adverse effects: Nystatin- topical use only. TOXIC because able to bind cholesterol. Decreases renal blood flow and can lead to permanent destruction of the basement membrane. 80% patients have nephrotoxicity

Resistance: Rare, decrease ergosterol in membrane

Question 5

Azoles- Fluconazole, Itraconazole, Ketoconazole

Answer 5

Mechanism: binds fungal P-450 enzyme(Erg11) blocking the production of the membrane protein ergosterol and causing the accumulation of lanosterol,
Fungistatic

Spectrum: Most widely used agent and spectrum varies by agent

Distribution: Orally available, substrate for efflux pump in the brain

Toxicity: Drug-Drug interactions, hepatotoxicity, neurotoxicity, alters hormone synthesis- avoid during pregnancy.

Resistance: Altered cytochrome P-450, Upregulation of efflux transporters

Don’t confuse with Metronidazole

Question 6

Allylamines- Terbinafine (Lamisil)

Answer 6

Mechanism: Fungicidal, Inhibits squalene epoxidase, which leads to toxic accumulation of squalene

Spectrum: Dermatophytes

Toxicity: Topical, drug interactions with CYP2D6 substrates

Resistance: Rare in human pathogens but could include decreased uptake, mutant binding site, and substrate for efflux transporters

Question 7

Flucytosine (5-FC): Nucleic Acid Synthesis Inhibitor

Answer 7

Mechanism: Antimetabolite selectively taken up and converted to 5-fluorouracil in fungi, interfering with DNA and RNA synthesis. Fungistatic

Spectrum: Narrow- Yeast
Candida albicans and Cryptococcus

Distribution: Oral, Penetrates CNS

Toxicity: Only partially selective for yeast can lead to bone marrow suppression- follow patient’s cell counts closely

Resistance: Loss of converting enzyme or transporters, often cotreat with amphotericin B to increase uptake and minimize the likelihood of developing resistance.

Question 8

Griseofulvin

Answer 8

Mechanism: Binds microtubules inhibits spindle leading to multinucleate cells, fungistatic

Spectrum: Dermatophytes (greater uptake)

Distribution: Lipids increase oral absorption and then concentrates in dead keratinized layer of the sin

Toxicity: Teratogenic (don’t use during pregnancy)

Resistance: change to beta-tubulin, need to take orally for months so if patient is not adherent resistance mutations are more likely to develop

Question 9

Echinocandins- caspofungin

Answer 9

Mechanism: Cell wall inhibitor blocks synthesis of Beta (1,3)-d-glucan polysaccharide. Fungicidal- Candida and Fungistatic- Aspergillus

Spectrum: Candida Albicans, systemic

Distribution: IV, large molecular wt prohibits CNS penetration

Toxicity: limited, fever, rash at site of injection
Resistance: Unknown (new drug)

Question 10

how fungi cause illness

Answer 10

0.1% of fungi cause human illness

Hypersensitivity reaction to the molds or spores
Mycotoxicoses- poisoning from toxins made by a fungus
Mycosis- fungus grows on or in the individual

Individuals with lowered cell-immunity have a dramatic increase in almost every type
of fungal infection

Question 11

Skin Mycoses

Answer 11

Cutaneous fungal infections
Malassezia (tinea versicolor)
Dermatophytes- Microsporum, Epidermophyton, Trichophyton

Subcutaneous fungal infections- infection through skin followed
by subcutaneous and/or lymphatic spread
Sporothrix

Opportunistic mycoses- infections in patients with immune deficiencies
Candida

Question 12

Diagnosis of Fungal Skin Infections:

Answer 12

Collect skin, nail, or hair
10% KOH (dissolves human tissue) can add stain View under microscope 40X

Wood’s lamp (UV-A light) under which some fungi fluoresce, PCR, culture

Question 13

Tinea versicolor (pityrosporium versicolor)

Answer 13

hypopigmentation and hyperpigmentation can both occur, generally no inflamation occurs

Malassezia furfur- yeast is part of normal flora converts to mold in disease, requires lipids so found predominantly in areas rich in sebaceous glands and in individuals 15-24 yrs old

Malassezia is also associated with seborrheic dermatitis, scaly (cradle cap)Diagnosis: KOH, Yellow-green by Wood’s lamp, cultures require olive oil

Treatment:
Topical therapy: Selenium sulfide or ketoconazole shampoo
Recurrence is common

Question 14

Dermatophytoses

Answer 14

extremely common (men>women) “ringworm”, “tinea” (not caused by a worm!)jock itch, athlete’s foot

Trichophyton
Microsporum
Epidermophyton

Pathogenesis:
Monomorphic molds enter through breaks in the skin, secrete proteases and keratinases
Fungal antigens cause inflammation (Kerion).
Grow best at 25°C unable to survive at 37°C so rarely see further invasion

Diagnosis: KOH test, grow on Sabouraud’s agar

Treatment: Topical griseofulvin, terbinafine or itraconazole 1 month
oral for nail infections but need to monitor for hepatotoxicity
Often reoccur

Question 15

Trichophyton rubum

Answer 15

most common cause of tinea pedis, serpentine lesion with central clearing anthrophilic- moist areas of skin, carried on clothing

Question 16

Tinea capitis 
Tinea barbae 
Tinea axillaris 
Tinea corporis 
Tinea cruris 
Tinea pedis 
Tinea unguium  	(onychomycosis)

Answer 16

Tinea capitis scalp
Tinea barbae beard
Tinea axillaris armpit
Tinea corporis body
Tinea cruris groin
Tinea pedis foot
Tinea unguium    nails	(onychomycosis)

Question 17

Microsporum

Answer 17

hair and skin
Microsporum canis- zoophilic (cats, dogs)
Microsporum fulvum- geophilic (soil)
Diagnosis:  Wood’s light blue-green
Spindle shape macroconidia

Epidermophyton floccosum different from other two species because lacks microconidia
Anthropophilic spread

Question 18

Sporothrix schenckii

Answer 18

dimorphic and causes “rose gardener’s disease” due to puncture wounds but most patients do not give this history

Pathogenesis: Fungi spread from initial lesion along lymphatic channels forming a chain of
nodular lesions, which can spread to bones and joints.
Diagnosis: Too few organisms for scraping, biopsy of lymph node culturing in Sabouraud agar
containing antibiotics, grow at different temperatures to confirm dimorphism
Treatment: Oral itraconazole for 3-6 months

Question 19

Candida albicans

Answer 19

commensal, most infections are endogenous

Superficial infections- Diaper dermatitis (more likely to by in the skin folds and around anas), at corners of the mouth (angular cheilitis), in toenail or edge of nails (paronychia), oropharyngeal (thrush)
Also responsible for vaginal and systemic infections

Diagnosis: Based on clinical appearance but can do skin scraping

Pathogenesis: Seeds in areas with less normal flora (antibiotic treatment)
Chronic mucocutaneous candidiasis may suggest individual has T cell disfunction
May also be a sign of diabetes

Treatment: Keep skin dry, Clotrimazole or other –azole cream

Question 20

Skin Mycoses

Answer 20

Cutaneous fungal infections
Malassezia (tinea versicolor)
Dermatophytes- Microsporum, Epidermophyton, Trichophyton

Subcutaneous fungal infections- infection through skin followed
by subcutaneous and/or lymphatic spread
Sporothrix

Opportunistic mycoses- infections in patients with immune deficiencies
Candida