MicroB Antimicrobials Anti-Fungal Agents

Question 1

3 examples of Echinocandins are
1. […]
2. Micafungin
3. Anidulafungin

Answer 1

3 examples of Echinocandins are
1. Caspofungin
2. Micafungin
3. Anidulafungin
Remember that they work by inhibiting glucan synthase complex (needed for cell wall formation)

Question 2

4 types of subcutaneous and systemic antifungal drugs -
1. […]
2. […]
3. […]
4. […]

The 3 types of cutaneous antifungal drugs
1. […]
2. […]
3. […]

Answer 2

4 types of subcutaneous and systemic antifungal drugs -
1. Amphotericin B (a polyene)
2. Flucytosine (an antimetabolite)
3. Caspofungin (an Echinocandin)
4. Triazoles (an Azole)

The 3 types of cutaneous antifungal drugs
1. Nystatin (a polyene)
2. Terbinafine (a squalene epoxidase inhibitor)
3. Imadazole (an Azole)

Question 3

5-Flucytosine is usually used in combination with […] for treating
- […]
- […]

Answer 3

5-Flucytosine is usually used in combination with amphotericin B (works synergistically to allow the drug to penetrate the cell) for treating
- candidiasis (septicemia, endocarditis, UTI)
- cryptococcosis (meningitis and pulmonary infections)
Another reason is partly also to minimize resistance (resistance to 5-FC can develop due to decreased levels of ANY of the enzymes in the conversion of 5-FC to its metabolites) (or increased synthesis of cytosine)

Question 4

5-Flucytosine works by inhibiting […] and […]

Answer 4

5-Flucytosine works by inhibiting protein synthesis and DNA synthesis
it is converted to

• 5-fluorouridine triphosphate (FUTP) and incorporated into fungal RNA in place of uridylic acid –> bye bye to protein synthesis
  OR
• 5-fluorodeoxyuridine monophosphate (FdUMP), inhibiting thymidylate synthase, a key enzyme for DNA synthesis –> bye bye to DNA synthesis~

5-FC enters fungal cells through cytosine specific permeases and is then converted, by cytosine deaminase, to its metabolically active form 5 fluorouracil (5-FU). Both proteins are absent in mammalian cells, however the conversion by gut bacteria and fungi of 5 FC to 5 FU can give rise to the adverse effects in the host

Question 5

Administration of 5-flucytosine is by […]

Penetration to CSF: Excellent

Answer 5

Administration of 5-flucytosine is by orally

Penetration to CSF: Excellent

Question 6

Adverse effect of 5-flucytosine (IMPT)
- […]
- […]

Answer 6

Adverse effect of 5-flucytosine (IMPT)
- Bone marrow suppression (very serious consequence)
- Hepatotoxicity (mild and reversible damage is common, monitor liver enzymes ALT and AST weekly)

Question 7

Adverse effects of Amphotericin B
1. …
2. […]
3. Hypotension
4. Thrombophlebitis (adding heparin can alleviate this problem)
5. Bone marrow suppression
6. Ototoxicity

Answer 7

Adverse effects of Amphotericin B
1. Fever and chills (shake and bake syndrome)(common)
2. Nephrotoxicity
3. Hypotension
4. Thrombophlebitis (adding heparin can alleviate this problem)
5. Bone marrow suppression
6. Ototoxicity

Question 8

Adverse effects of echinocandins

[…]

Answer 8

Adverse effects of echinocandins

MINIMAL yay! rarely leads to drug discontinuation…. but if you must name some…..

1. GI related symptoms
2. fever
3. chills
4. rashes
5. skin flush
6. thrombocytopenia

Question 9

Adverse effects of terbinafine
1. GI disturbance
2. Headache
3. Rash
4. Herpatic failure
5. Exerbation of […]

Contraindication: DONT GIVE TO […]

Answer 9

Adverse effects of terbinafine
1. GI disturbance
2. Headache
3. Rash
4. Herpatic failure
5. Exerbation of autoimmune disease (SLE)

Contraindication: DONT GIVE TO Nursing mothers (it concentrates in breastmilk)

Question 10

Amphotericin B is a naturally occuring […] antifungal and is effective used against […], […], […], […]

It is administered by
[…]

Answer 10

Amphotericin B is a naturally occuring polyene antifungal and is effective used against candida albicans, cryptococcus, aspergillus, histoplasmosis

It is administered by
Topical or IV infusion (negligible oral absorption)

TLDR, its useful against the medically important fungal infections

usually used alongside nystatin in a variety of oral formulation.

Question 11

Amphotericin B is insoluble in water and must be coformulated with either
- […], or
- […]

The liposomal preparations have reduced […] toxicity but are […]

Answer 11

Amphotericin B is insoluble in water and must be coformulated with either
- Sodium Deoxycholate, or
- Artificial lipids to form liposomes

The liposomal preparations have reduced renal toxicity but are costly

Despite the low levels of the drug excreted in the urine, conventional amphotericin B (ie not the lipid formulations) causes renal vasoconstriction and can reduce the glomerular filtration rate by more than half.

Concurrent therapy with other nephrotoxic agents can increase the risk further. Renal function usually returns with discontinuation of the drug. Hydrate patients adequately (this seems to be the solution for most nephrotoxic drugs LOL)

Question 12

Azoles can be split into 2 categories
1. Triazoles (given […] for […] infection)
2. Imidazoles (given […] for […] infection)

Answer 12

Azoles can be split into 2 categories
1. Triazoles (given **orally/IV **for systemic infection)
2. Imidazoles (given topically for cutaneous infection)
Predominantly fungistatic~

Question 13

Caspofungin (a echinocandin) is one of the first line option for […] and second line option for […]:

Answer 13

Caspofungin (a echinocandin) is one of the first line option for candidiasis and second line option for invasive Aspergillosis (in patients who have failed or cannot tolerate amphotericin B or an azole):

Question 14

DDI: All azoles are […], hence they enhance activity of drugs metabolised by CYP 450 including […]

Answer 14

DDI: All azoles are hepatic CYP450 3A4 isoenzyme inhibitors, hence they enhance activity of drugs metabolised by CYP 450 including warfarin, cyclosporine and oral hypoglycemic agents

Question 15

Echinocandins are administered by […]

Answer 15

Echinocandins are administered by IV (lack oral bioavailability)
Undergo extensive protein binding (>97%) and are unable to penetrate into CSF

Question 16

Echinocandins have potent activity against
1. […]
2. […]

Answer 16

Echinocandins have potent activity against
1. most Candida species (including those resistant to azoles)
2. Aspergillus
First line for candidiasis
Second line for aspergillus

Broad spectrum activity~

Question 17

Example of Polyenes:
1. […] (systemic)
2. […] (cutaneous)

Example of Echinocandins
1. […] (systemic)

Example of Azoles:
1. […] (systemic)
2. […] (cutaneous)

Answer 17

Example of Polyenes:
1. Amphotericin B (systemic)
2. Nystatin (cutaneous)

Example of Echinocandins
1. Caspofungins (systemic)

Example of Azoles:
1. Triazoles - Fluconazole, Itraconazole, Voriconazole (systemic)
2. Imidazoles - Clotrimazole, Miconazole (cutaneous)

Question 18

Fluconazole is the least active amongst the triazoles.

very useful treatment for: […]

Other things it can treat include
1. fungal meningitis (most of them)
2. Cryptococcus neoformans
3. Candidemia and candidiasis
4. Histoplasmosis
5. Blastomycosis

Answer 18

Fluconazole is the least active amongst the triazoles.

very useful treatment for: vulvovaginal candidiasis - SINGLE DOSE oral treatment

Other things it can treat include
1. fungal meningitis (most of them)
2. Cryptococcus neoformans
3. Candidemia and candidiasis
4. Histoplasmosis
5. Blastomycosis

Contraindications
Azoles are considered teratogenic, and they should be avoided in pregnancy unless the potential benefit outweighs the risk to the fetus

Question 19

Imidazoles have a wide range of activity against
1. Epidermophyton
2. Microsporum
3. Trichophyton
4. Candida
5. Malassezia (depending on the agent)

Administered in the form of […]

The topical imidazoles have a variety of uses, including tinea corporis tinea cruris tinea pedis and oropharyngeal and vulvovaginal candidiasis

Answer 19

Imidazoles have a wide range of activity against
1. Epidermophyton
2. Microsporum
3. Trichophyton
4. Candida
5. Malassezia (depending on the agent)

Administered in the form of Cream, lotion, powder, pessary, troche(lozenges)

The topical imidazoles have a variety of uses, including tinea corporis tinea cruris tinea pedis and oropharyngeal and vulvovaginal candidiasis

Adverse effects: Topical use is associated with contact dermatitis, vulvar irritation, and edema

Question 20

In patient who have blastomycosis, nonmeningeal histoplasmosis or aspergillosis but are intolerant to amphotericin B,

can administer […]

Answer 20

In patient who have blastomycosis, nonmeningeal histoplasmosis or aspergillosis but are intolerant to amphotericin B,

can administer Itraconazole

Question 21

Nystatin is administered […] for treatment of […] or […]

used treatment for
1. oral/GI fungal infections
2. […]
3. cutaneous candida infections

Answer 21

Nystatin is administered Orally “swish and swallow”/”swish and spit” for treatment of vulvovaginal candidiasis (intravaginally) or cutaneous candidiasis (topical)

used treatment for
1. oral/GI fungal infections
2. oropharyngeal candidiasis aka THRUSH
3. cutaneous candida infections

DO NOT GIVE IV!!!!!! It’s toxic (acute infusion related adverse effects and nephrotoxicity)

Question 22

Terbinafine is administered […]

IMPORTANT
[…] administration for tinea capitis(scalp) or tinea unguium (nails) because you want it to accumulate in […]

Answer 22

Terbinafine is administered Oral and Topical

IMPORTANT
ORAL administration for tinea capitis(scalp) or tinea unguium (nails) because you want it to accumulate in keratin

Applying it over the nail….doesnt work yeah?

Anw it works cuz it is highly protein bound and is deposited in the skin, nails, and adipose tissue

Question 23

Terbinafine is especially active against the species […]

Answer 23

Terbinafine is especially active against the species Trichophyton

Question 24

Terbinafine works by inhibiting […]. Accumulation of […] increases membrane permeability + compromised fungal cell membrane = death of fungal cell

Answer 24

Terbinafine works by inhibiting **squalene epoxidase (hence inhibit synthesis of ergosterol). **Accumulation of squalene increases membrane permeability + compromised fungal cell membrane = death of fungal cell

Question 25

The 2 examples of Imidazoles
1. […]
2. […]

Answer 25

The 2 examples of Imidazoles
1. Clotrimazole
2. Miconazole
DON’T CONFUSE WITH COTRIMOXAZOLE (anti-folate drug) PLEASEEEE

Question 26

the 3 triazoles are
1. […]azole
2. […]azole
3. […]azole

Answer 26

the 3 triazoles are
1. Fluconazole
2. Itraconazole
3. Voriconazole

Question 27

The three main classes of anti-fungal drugs and their mechanisms of action

1. […] (Amphotericin B, Nystatin) - Binds to […] and causes […] to develop in cell membrane
2. […] (Imidazoles,Triazoles) - inhibits […] synthesis by inhibiting […]
3. […] (caspofungin,micafungin,anidulafungin) - inhibits […] synthesis by inhibiting […]

Answer 27

The three main classes of anti-fungal drugs and their mechanisms of action

1. Polyenes (Amphotericin B, Nystatin) - Binds to ergosterol and causes pores to develop in cell membrane
2. Azoles (Imidazoles,Triazoles) - inhibits ergosterol synthesis by inhibiting lanosterol 14a-demethylase
3. Echinocandins (caspofungin,micafungin,anidulafungin) - inhibits cell wall synthesis by inhibiting b-1-3-glucan synthase

Question 28

Unlike bacteria, fungi are […], with rigid cell walls composed largely of […] rather than peptidoglycan

Unlike cholesterol found in mammalian membranes, Fungal cell membrane contains […]

Answer 28

Unlike bacteria, fungi are eukaryotic, with rigid cell walls composed largely of chitin rather than peptidoglycan

Unlike cholesterol found in mammalian membranes, Fungal cell membrane contains ergosterol

These structural characteristics are useful in targeting therapeutic agents against fungal infections

Fungal infections (mycoses/mycotic infections) are generally resistant to antibiotics, and, conversely, bacteria are resistant to antifungal agents.

Susceptible populations include the immunocompromised patients (e.g. transplant and HIV patients)

Question 29

Voriconazole is one of the first line treatment for […]

Answer 29

Voriconazole is one of the first line treatment for
Invasive asperigillosis
Second line would be amphotericin B