Dr. Stahelin Antifungals

Question 1

Opportunistic pathogens

Answer 1

Absidia corymbifera, Aspergillus fumigatus, candida albicans, cryptococcus neoforman, pneumocycstis jiroveci, rhizomucor pusillus, rhizopus oryzar

Question 2

Dermatophytosis

Answer 2

• classic skin and hair infections (ringworm, athlete’s foot, jock itch, etc)
• Epidermophyton, Trichophyton, and microsporum are the 3 genera of mold that grown on keratin on a living host
• causes a series of conditions called tineas

Question 3

Onchomycosis

Answer 3

non-dermatophyte nail infections or any fungal nail infection caused by any fungus

Question 4

Amphotericin B

Answer 4

• Polyenes
• MOA: binds to ergosterol and withdraws ergosterol from the cell membrane in fungal cells
• reason for specificity: mammalian and bacterial cell membranes contain cholesterol
• fungicidal
• Structure: contains both acidic and basic groups in the structure. Contains a lipophilic polyene region and hydrophilic polyalcohol region (amphiphilic). Contains a macrolide ring.
• mycosamine group: required for binding to ergosterol
• hydroxyls are critical for pore formation and binding to cholesterol

Question 5

amphotericin B major toxicities

Answer 5

• infusion-related - fevers, chills, muscle spasms, vomiting, headache, and hypotensions. Premedicated with diphenhydramine and/or tylenol
• Renal damaged- reduced renal perfusion (reversible) and real tubular injury (irreversible)

Question 6

Amphotericin B SOA

Answer 6

candida albicans, cryptococcus neoformans, histoplasma capsulatum, blastomyces dermatitidis, coccidioides immitis, and aspergillu fumigatus

Question 7

Terbinafine

Answer 7

• allylamines
• MOA: disrupts ergosterol synthesis by inhibiting squalene epoxidase. Squalene imbeds into the membrane and can lead to toxicity and fungal cell death
• reason for specificity: 2500 fold selectivity for fungal enzyme compared to mammalian enzyme
• SOA: mostly effective against dermatophytes (epidermophyton, trichophyton, and microsporum), especially onychomycosis
• fiungicidal

Question 8

Azoles

Answer 8

• MOA: inhibition of 14-alpha-demethylase, that prevents the binding and activation of molecular oxygen by cytochrome P450 which prevents the conversion of lanosterol to ergosterol. The build-up of toxic sterols leads to damage to the cell membrane and the inability of fungi to continue to spread
• reason for specificity: humans use the same enzyme to make cholesterol for our cell membranes but fungal enzymes are more sensitive
• Fungistatic
• azole antifungals are metabolized by CYP450 enzymes

Question 9

Miconazole

Answer 9

• first described azole antifungals
• differ in distance of azole group from asymmetric carbon
• the alteration changes the SOA, interactions with CYP, and route of administration

Question 10

Ketoconazole

Answer 10

• first azole with sufficient oral bioavailability to be used clinically for deep tissue infections
• based on miconazole: dioxolane ring on asymmetric carbon and reduced metabolism by CYP3A4
• potent inhibitor of CYP3A4

Question 11

Itraconazole

Answer 11

• based on ketoconazole: triazole instead of imidazole, modified substituent on dioxolane ring, improved specificity for fungal P450 enzyme
• extensively metabolized by CYP3A4 in the liver
• variable absorption
• bad taste

Question 12

Itraconazole SOA

Answer 12

Similar SOA to fluconazole plus aspergillus. Not as broad as voriconazole, posaconazole, or isavuconazole

• azole of choice for Histoplasma, Blastomyces, and sporothrix
• extensively used for dermatophytoses and onychomycosis

Question 13

Fluconazole

Answer 13

• substantially modified ketoconazole: triazole in place of imidazole, F in place of Cl on benzene ring, hydroxyl and 2nd triazole on asymmetric carbon, dioxolane ring eliminated.
• 80% excreted by kidney and unchanged
• high solubility and bioavailability
• penetrates CSF

Question 14

Fluconazole SOA

Answer 14

• good activity against C. albicans and many other candida spps (most commonly used for mucocutaneous candida)
• some candida spps are naturally resistant (C. krusei, C. glabrata)
• Cryptococcus Neoformans - azole of choice for treatment and prophylaxis of cryptococcal meningitis

Question 15

Voriconazole

Answer 15

• based on fluconazole: maintains triazole, hydroxyl, and fluorine substituents. 2nd triazole replaces with fluoropyrimidine ring. Added methyl group - improved binding to fungal 14 alpha-demethylase and increased SOA.
• Metabolized extensively in liver by CYP2C19 > CYP3A4 > CYP2C9 (CYP2C19 polymorphisms can alter levels)
• highly soluble and high oral bioavailability
• CSF levels ~1/2 of plasma levels
• teratogenic in animals and is contraindicated in pregnancy (category D)
• side effects: visual disturbances

Question 16

Voriconazole SOA

Answer 16

• active against cadida spps including some fluconazole-resistant strains
• extended SOA against yeasts, cryptococcus, and molds including aspergillus
• may be more effective against aspergillus than amphotericin B

Question 17

Posaconazole

Answer 17

• derived from itraconazole: has a furan ring that alters and increases the spectrum of activity. Fluorine replaces carbon.
• broad spectrum of activity: similar to voriconazole but with better activity against filamentous fungi such as zygomycetes
• oral suspension and IV administration
• metabolized in the liver by glucuronidation

Question 18

Isavuconazole

Answer 18

• structurally similar to voriconazole
• broad spectrum of activity: similar to voriconazole but also zygomycetes
• water-soluble pro-drug: cyclodextrin not required for solubility, reduced nephrotoxicity relative to voriconazole.
• long half-life
• prodrug is isavuconazonium
• cleaved by plasma esterases
• fewer adverse effects and drug-drug interactions than voriconazole
• SOA: similar to voriconazole and approved for tx of invasive aspergillosis and mucormycosis

Question 19

Echinocandins

Answer 19

• lipopeptides
• all must be administered by IV due to poor bioavailability
• cyclic hexapeptides with long modified fatty acid chains
• MOA: inhibit the synthesis of beta(1,3)-glucan cell wall component. Beta(1,3)-glucan synthase is the target enzyme.
• mammalian cells lack this activity
• fungicidal
• broad spectrum of activity: synergistic with voriconazole and amphotericin B.
• No cross-resistance with other antifungals and not metabolized by liver CYPs
• degraded in blood and tissues

Question 20

Caspofungin

Answer 20

• echinocandins
• disseminated and mucocutaneous candida
• salvage therapy in patients with aspergillosis who fail to respond to amphotericin B

Question 21

Micafungin

Answer 21

• echinocandins
• mucocutaneous candida
• candida prophylaxis in bone marrow transplant patients

Question 22

anidulafungin

Answer 22

• echinocandins
• esophageal candidiasis, invasive candidiasis
• has the longest half-life and no known drug interactions

Question 23

Flucytosine

Answer 23

• antimetabolite (pyrimidine analog)
• MOA: inhibits thymidylate synthase and interferes with proteins synthesis. Flucytosine is first converted by cytosine deaminase to 5-FU. 5-FU is phosphorylated to form 5-FdUMP and 5FdUMP mimics dUMP. 5FdUMP is a substrate, a competitive inhibitor, and a suicide inhibitor of thymidylate synthase. no dTMP can be produced and thus inhibits viral DNA synthesis.
• mammalian cells are unable to convert flucytosine to active metabolite.
• Synergizes with amphotericin B
• penetrates well into all fluid compartments including CSF

Question 24

flucytosine ADR

Answer 24

• removed by kidney so renal impairment can lead to toxicity
• intestinal flora can metabolize to 5-FU anti-cancer drug and monitoring of levels is necessary when combined with amphotericin B

Question 25

flucytosine SOA

Answer 25

cytptococcus neoformans (combined with amphotericin B for cryptococcal meningitis), some candida species, aspergillus, most filamentous fungi are not susceptible

Question 26

Griseofulvin

Answer 26

• produced by a strain of penicillium
• disrupts fungal microtubules
• fungistatic
• must be given orally - becomes incorporated in keratin precursor cells
• used for dermatophytes
• inactive against yeast, mold, and dimorphic fungi

Question 27

Tavaborole

Answer 27

• inhibits leucyl transfer RNA synthetase (LeuRS) in thus inhibiting protein synthesis
• boron is essential for activity
• topical treatment if onychomycosis