L12 - Treatment of Fungal Diseases

Question 1

What are the four main classes of antifungals? - Give an example

Answer 1

Polyenes (Amphotericin B)
Azoles (Voriconazole)
Echinocandins (Caspofungin)
Allylamines (Terbinafine)

Question 2

What is the MoA of Polyenes?

Answer 2

Polyenes bind to Ergosterol in the cell membrane, weakening it

Question 3

What is the MoA of Azoles?

Answer 3

Azoles inhibit the conversion of Lanosterol to Ergosterol (c14a-demthylase)

Question 4

What is the MoA of Allylamines?

Answer 4

Allylamines inhibit the conversion of Squalene to Lanosterol (Squalene epoxide)

Question 5

What is the MoA of Echinocandins?

Answer 5

Echinocandins inhibit glucan synthesis in the cell wall (B-1,3-D-glucan synthase)

Question 6

What is the MoA of 5-Flucytosine?

Answer 6

5-Flucytosine is an antimetabolite pyrimidine analogue

Question 7

Define selective toxicity

Answer 7

The ability to be toxic to microbial cells but not host cells

Question 8

What are the problems with selective toxicity?

Answer 8

Sterols (cholesterol) are present in host plasma membranes
CYP450 system in host hepatocytes
Nucleic acids in host cells

Question 9

How can we achieve selective toxicity?

Answer 9

Topical application

Target specificity

Question 10

Describe Amphotericin B toxicity - Acute reactions

Answer 10

30 mins post infusion
Chills, fever, SoB, drop in BP, aches
Peaks @ 1h, lasts <4h
Induction of Prostaglandin E2

Question 11

How can we treat for Amphotericin B toxicity? - Acute reactions

Answer 11

Test doses and escalate slowly

Pre-medicate (NSAIDs/steroids)

Question 12

Describe Amphotericin B toxicity - Renal toxicity

Answer 12

Vasoconstriction of afferent renal aa
K, Mg, HCO3- loss
Decreased EPO
Loss of nephrons

Question 13

How can we treat for Amphotericin B toxicity? - Renal toxicity

Answer 13

Regular renal monitoring
Electrolyte replacement
Amiloride

Question 14

Describe Amphotericin B toxicity - Rarer symptoms

Answer 14

Anorexia, nausea, vomiting
Phlebitis
Gradual anaemia (decreased EPO)
Thrombocytopaenia, leucopenia, coagulopathy
Tinnitus, vertigo, seizures, encephalopathy
Anaphylaxis/allergy

Question 15

What is an appropriate dose of AmB?

Answer 15

3-5mg/kg

Question 16

What are the three lipid formulations of Amphotericin B?

Answer 16

Liposomal AmB (L-AmB)
AmB colloidal dispersion (ABCD)
AmB lipid complexes (ABLC)

Question 17

Describe L-AmB

Answer 17

60-70nm vesicles

Question 18

Describe ABCD

Answer 18

~115nm diameter discs

Question 19

What is the disadvantage of lipid formulations of AmB?

Answer 19

Expense

Question 20

Why do we use lipid formulations of Amphotericin B?

Answer 20

AmB is released by preferential affinity to Ergosterol/action of phospholipase, avoiding toxicity

Question 21

Describe ABLC

Answer 21

1600-11000nm ribbons

Question 22

Describe the Antifungal spectrum

Answer 22

AmB - Largely effective (Scedosporium)
Fluc - Rarely effective
Itra - Somewhat effective
Vori - Largely effective

Question 23

How does resistance to AmB arise?

Answer 23

Alteration of Ergosterol (reduces fungal fitness)

Question 24

How does resistance to Azoles arise?

Answer 24

Altered c14a demthylase

Efflux mechanisms

Question 25

How does resistance to 5-Flucytosine arise?

Answer 25

Decreased permeability Altered phosphorylation Resistance only common in monotherapy

Question 26

Describe the formulation of Echinocadins

Answer 26

Lipopetide side chains determine solubility | i.v. route only

Question 27

What is the activity of Echinocandins restricted to?

Answer 27

``` Candida spp (cidal) Aspergillus spp (static) ```

Question 28

What are the side effects of Echinocandins?

Answer 28

``` Phlebitis Fever Headache Hepatotoxicity Haemolysis ```

Question 29

Define mycoses

Answer 29

Mild to severe infections with fungi

Question 30

Give examples of the superficial mycoses

Answer 30

Skin - Dermatophytosis Nails - Onychomycosis Mucous Membranes - Candidasis

Question 31

Give examples of the deep mycoses

Answer 31

Invasive candidasis Aspergillosis Cryptococcosis

Question 32

What moulds cause dermatophytosis? - Tineas

Answer 32

Trichophyton Microsporum Epidermophyton

Question 33

What yeasts cause dematophytosis?

Answer 33

Malassezia

Question 34

What predisposes patients to invasive candidasis?

Answer 34

Indwelling devices Damaged mucosae Immunocompromised

Question 35

What antifungals are used to treat invasive candidasis?

Answer 35

AmB Fluconazole Caspofungin Micafungin

Question 36

What antifungals are used to treat aspergillosis?

Answer 36

AmB Itraconazole Voriconazole Caspofungin

Question 37

What problem does cryptococcus cause in HIV?

Answer 37

Meningitis

Question 38

What antifungals are used to treat cryptococcus?

Answer 38

AmB +/- 5-Flucytosine

Question 39

What antifungals are used to treat endemic mycoses?

Answer 39

AmB | Itraconazole