Antifungal Resistance Primer

Question 1

Amphotericin B

•Mechanism of Action

Answer 1

– binds to ergosterol in the fungal cytoplasmic membrane

Question 2

Amphotericin B

•Mechanism of resistance

Answer 2

– ?Less permeable cell wall

Question 3

Amphotericin B

• Resistance includes:

Answer 3

– Scedosporium apiospermum (Pseudallescheria boydii), Lomentospora (Scedosporium) prolificans

– Some isolates of Candida lusitaniae

– Some Fusarium species

– Aspergillus terreus

Question 4

Azoles:

• Mechanism of action

Answer 4

– Blocks ergosterol synthesis by inhibiting sterol C14 demethylation.

Question 5

Azoles:

• Active against almost all yeasts (fluc preferred)

Answer 5

• Candida species
• Cryptococcus

Question 6

Azoles:

• Active against dimorphic fungi (itraconazole preferred)

Answer 6

• Histoplasma, Coccidioides, Blastomyces
• Paracoccidioides, Penicillium marneffei, Sporothrix

Question 7

Azoles:

• Active Against Some Molds

Answer 7

– Voriconazole‐ aspergillus

– Posaconazole‐ aspergillus and mucor

– Isavuconazole‐ aspergillus and some mucor species

Question 8

Azoles:

• Mechanism of resistance

Answer 8

– increased drug efflux, particularly Candida glabrata

– increased production of sterol C14 demethylase

– mutations in ERG11/ Cyp51, which codes for the target enzyme

Question 9

Azoles:

• Azole‐Resistant species

Answer 9

– C. krusei and some C. glabrata

– Fluconazole has no activity against molds

– Voriconazole has no activity against Mucorales

Question 10

Echinocandins:

• Mechanism of action

Answer 10

– block cell wall formation by inhibiting (1,3)–beta‐D‐glucan synthase.

Question 11

Echinocandins:

• Mechanism of resistance

Answer 11

– “Hotspot” mutations in the (1,3)‐beta‐D‐glucan synthase genes, FKS1 and FKS2 of Candida species.

Question 12

Echinocandins:

• Susceptible:

Answer 12

– All wild type Candida and most Aspergillus species

– Candida parapsilosis and Candida guilliermondii have higher MIC but clinical efficacy good with C. parapsillosis

Question 13

Echinocandins:

• Resistance

Answer 13

– Cryptococcus and Trichosporon species

– Most molds other than Aspergillus

– Candidiasis during very prolonged therapy (secondary resistance)

Question 14

Flucytosine (5‐Fluorocytosine)

• Mechanism of Action

Answer 14

– Prodrug which is deaminated by susceptible fungi to 5‐ fluorouracil, a nucleotide analogue that inhibits formation of DNA and RNA.

Question 15

Flucytosine (5‐Fluorocytosine)

• Susceptible

Answer 15

– All Candida and Cryptococcus species are initially susceptible

– Rapid appearance of resistance, mostly due to mutations in FCY1 (cytosine deaminase) and FUR1 (uracil phosphoribosyl transferase)