Antifungals

Question 1

when you think Fungus you generally think of?

Candida spp. is a ?

Cryptococcus spp. is a ?

Aspergillus spp. is a ?

Answer 1

yeast and mold

Candida spp. is a yeast

Cryptococcus spp. is a yeast

Aspergillus spp. is a mold

Question 2

What type of patients are at risk for fungal infections?

Answer 2

-Increasing number of immunocompromised and immnocompetent

-Can occur in immunocompetent patients as well
→ patients that have chronic catheters or chronic antibiotic use

Question 3

What are the different routes of transmission for fungal infections?

Answer 3

• Respiratory→ pores inhalation (aspergillus is present in the soil)
• Traumatic implantation
• Direct contact (dermatoid infections)

Question 4

What are the different categories of anti fungal agents available ?

Answer 4

• Allylamines (topical agents)
• Polyenes
• Azoles
• Echinocandins
• Miscellaneous→ Flucytosine

Question 5

Allylamines:

1. ) Forumulations available?
2. ) Indications?
3. )MOA?

Answer 5

1.) Topical agents

2. ) Indications:
   - Tinea cosporis (ring worm)
   - Tinea pedis (athlete’s foot)
   - Tinea cruris (jock itch)
   - Onychomycosis (terbinafine) → nail fungus
3. )MOA:
   - inhibition of squalene epoxidase → reducing fungal cell membrane ergosterol synthesis (allylamines-ES stands for squalene epoxidase)

Question 6

Terbinafine:

1. ) Excretion?
2. )Monitoring?
3. ) Great for treating fungal infections of the?

Answer 6

1.) Excretion: Renally eliminated, caution in hepatic impairment

2.) Monitoring:
-SCr
-LFTs
*at baseline and throughout the treatment)
-CBC
→ only if > then 6 weeks of tx in immunodeficient patients

3. ) great for treating fungal infections of the
   - fingernails → esp nail fungus
   - toenails→ esp nail fungus
   - tinea

Question 7

What is the mechanism of action for azoles?

Answer 7

• Inhibition of 14 alpha-demethylase which converts lanosterol to ergosterol → disruption in cell membrane synthesis
• also blocks steroid synthesis in humans

Question 8

What are the indications for use of Imidazoles?

Answer 8

Indications:
􏰀 Tinea cotporis
􏰀 Tinea pedis
􏰀 Tinea cruris
􏰀 Oropharyngeal candidiasis 
􏰀 Vulvovaginal candidiasis

Question 9

What Imidazole agents do we have available?

Answer 9

􏰀 Ketoconazole
􏰀 Clotrimazole
􏰀 Miconazole

Question 10

Ketoconazole:

1. ) Imidazole or Triazole?
2. ) Effective against? High failure rate in?
3. ) Excretion?

Answer 10

1.) Imidazole

2. )Effective against:
   - Candida spp.
   - Blastomycosis,
   - Histoplasmosis(high failure rates)

3.) Excreted in feces

Question 11

Ketoconazole:

2. ) CYP interactions?
3. ) Considerations

Answer 11

2. ) -CYP450 3A4 substrate→ CYP inhibition = drug interactions!!!
3. ) Needs acidic gastric pH for absorption-think interactions with tums and omperazole (will make t & o not work)

Question 12

Ketoconazole:

1. ) Side Effects?
2. ) C/I’s?

Answer 12

1. ) Can cause QTc prolongation → black box warning

2. ) C/I in patients with hepatic impairment

Question 13

1. )What Triazole agents do we have available?

2. ) What do we commonly associate Triazole agents with?

Answer 13

1.)
􏰀 Fluconazole
􏰀 Itraconazole 
􏰀 Voriconazole 
􏰀 Posaconazole 
􏰀 Isavuconazole

2.) Systemic invasive fungal infections (REALLY BAD INFECTIONS)

Question 14

Triazoles:

1. ) MOA?
2. ) Fungicidal or fungal static?

Answer 14

1. ) MOA: inhibition of CYP450-34A and sterol C-14alpha-demethylation
2. ) Primarily fungistatic

Question 15

How are the newer triazoles different from the older triazoles?

Answer 15

The newer triazoles have....
 less hormonal inhibition, 
broader spectrum,
 less toxic, 
better tissue distribution

Question 16

Fluconazole: (Diflucan)

1.) Indication?

Answer 16

1. ) Indication:
   - Candidiasis: invasive →(oroesophageal/urogenital/vulvovaginal)

• ProphylaxisinBMTrecipients/txtpatients
• Cryptococcosis: consolidation phase (used after initial treatment)

Question 17

Fluconazole:

1. ) DDI’s?
2. ) This drug is beneficial also for _____ b/c it can ……?
3. ) Side effects and dose adjustments?

Answer 17

1. ) CYP interactions:
   - Minor inhibition of CYP 3A4
   - Moderate inhibitor of CYP 2C9

2.)Fungal meningitis because it can cross the BBB
→ Can penetrate the CNS

3. )Side effects and dose adjustments:
   - Needs to be adjusted in renal failure
   - Check QTc
   - Pt’s may experience Alopecia

Question 18

Itraconazole:

1. ) Indication?
2. ) What DDI’s do you have to be aware of and why?

Answer 18

1.)Indication:
-Candidiasis: oropharengeal and esophageal
→ Maybe a step down therapy in Aspergillosis ( NOT 1st line!)

2.) warfarin b/c this drug is ***99% protein bound

Question 19

Itraconazole:

1.) Formulations available? What do you have to considerations when giving the dose?

Answer 19

1. )
   - Available in capsules in solution BUT, CANNOT interchange
   - Capsules need to be given w/ meal
   - Solution should be given on an empty stomach and is preferred formulation

Question 20

Itraconazole:
1.) Side effects?

2.) C/I’s?

Answer 20

1. )
   - HTN
   - Edema
   - Hypokalemia
   - QTc-prolongation

2.) Cardiac Patients- QTc prolongation

Question 21

Voriconazole:

1.) Indication?

Answer 21

1. )Indication: (you “vori” because they must be really sick)
   - Resistant Candida infections
   - Aspergillosis

Question 22

Voriconazole:

1. ) Bioavailabilty?
2. )Additional Info?
3. ) DDI’s?

Answer 22

1.)
-95% oral bioavailability, BUT:
→ Can be unpredictable
→ Reduced wT/ high fat meal
→ Administer 1 hour before or one hour after a meal

2. ) Large Vd and good CNS penetration
3. ) Substrate and inhibitor of CYP3A4, CYP2C9, and CYP2C19→ DRUG INTERACTIONS!!!

Question 23

Voriconazole:

1. ) Monitoring?
2. ) Side effects?

Answer 23

1.)Monitoring: Cmin → for severe infections
→ If Level id > 5mg/L = CNS toxicity

• SCr, electrolytes, LFTs, ophthalmic exam if therapy >4weeks
• QTc so EKG

2. ) Side Effects: Not Lying Very Hot Hot S**
   - N/V/D
   - Liver dysfunction
   - Visual and auditory abnormalities
   - HA
   - Hepatotoxicity
   - Steven Johnson syndrome

Question 24

Posaconazole:

1.) Indication?

Answer 24

1. )Indication:
   - Resistant Candida infections
   - Aspergillosis
   - Mucorales and other mold infections → *only azole indicated for this *

Question 25

Posaconazole: 1.) Oral bioavailability

Answer 25

1.) Oral bioavailability: >90% w/ high fat meal meat → so pt should be taking this med with a high Fat meal

Question 26

Posaconazole: 1. ) Where does this drug extensively distribute? 2. ) DDI's?

Answer 26

1.) Extensive distribution and penetration into tissues/ potentially therapeutic CSF levels 2. ) - Potent inhibitor of CYP3A4 - Inhibitor and substrate of P-glycoprotein → ex: apixaban - ↓ absorption w/ PPIs, H2RA

Question 27

Posaconazole: 1. ) Which formulation should you administer and why? 2. )Monitoring

Answer 27

1. ) - Start with IV formulation because oral has slow onset (No PO -POsaconazole cause slOW) so use IV to get it quickly → loling 2.) Monitoring -SCr, electrolytes, and LFTs → No renal adjustment

Question 28

Posaconazole: Side effects?

Answer 28

- GI - HA - rare hepatotoxicity*** - QTc prolongation**** - hemolytic uremic syndrome***

Question 29

Isavuconazole: 1. ) Indication? 2. ) Excretion? 3. ) Half life?

Answer 29

1. ) Indication: - Invasive Aspergillosis - Mucormycosis 2. ) Excretion: - Cleared primarily via fecal excretion 3.)Half-life: 130HRS!!!!

Question 30

Isavuconazole: 1. )How is the drug administered? 3. ) C/I's?

Answer 30

1.)Administered as a pro-drug: isavuconazonium*** 3.) → Contraindicated with potent 3A4 inhibitors and inducers → Contraindicated in familial short QT syndrome

Question 31

Isavuconazole: 1. ) DDI's? 2. ) Side Effects?

Answer 31

1. )DDI's: - inhibits CYP3A4, P-glycoprotein, and OCT-2 2. )Side Effects: - GI - ***Hypokalemia*** - Elevated LFTs - HA

Question 32

Polyenes: 1. ) MOA? 2. ) Agents available?

Answer 32

1.) MOA: bind w/ sterols in the fungal cell membrane ( principally ergosterol), leads to the cell contents to leak out and ultimately cell death 2. ) - Nystatin - Amphotericin B

Question 33

Nystatin: 1. ) Indication? 2. ) Formulations available?

Answer 33

1. ) Indication: - Candida spp. only!→ used for thrush 2.) Comes as liquid formulation and topical → No IV b/c too toxic for systemic administration

Question 34

Amphotercin B: 1. )What type of agent is it?/What does it cover? 2. ) How many formulations available? how do they travel through the blood stream?

Answer 34

1. ) Broad spectrum agent: - Most Candida spp. and Aspergiluss spp. - Most fungi except Fusarium spp. and A. terreus 2.) 3 diff. formulations available-99% protein bound

Question 35

Amphotercin B: 1.) What does Amphoteric mean in regards to this drug?

Answer 35

1.) Amphoteric → Soluble in both basic and acidic environments → Insoluble in water

Question 36

AmB-d: 1.) Side Effects? (8 side effects) how do you prevent 2 out of the 8 side effects

Answer 36

1.) Side Effects: -Neprotoxic! (d in AmB-d for damages kidneys) → ARF in 50% of patients -Infusion- related rxn's → Pre-medicate w/ APAP or IBU, diphenhydramine +/- steroids develop → Rigors: meperidine - Thrombophlebitis, - cardiac arrhythmias, - rash - decrease in GFR ( vasoconstrictive effect on renal arterioles) - Decreases erythropoietin production - Electrolyte derangement

Question 37

AmB-d: 1.) Monitoring?

Answer 37

``` Monitor: SCr, BUN, electrolytes, CBC, LFTs ```

Question 38

L-AmB: 1. ) Differences from AmB-d: (4 things) 2. ) Side effects?

Answer 38

1.) 􏰀 Less nephrotoxic-(L in L-AmB stands for Less Nephrotoxic) 􏰀 Reduced frequency and severity of infusion related reactions 􏰀 Higher Cmax and larger AUC 􏰀 Higher tissue concentrations vs other AmB formulations 2. ) Side effects: - Hepatotoxicity

Question 39

Echinocandins: 1. ) Indication? 2. ) MOA?

Answer 39

``` 1.) Indication: 􏰀 Invasive candidiasis 􏰀 Empiric coverage in neutropenic fever → Fungicidal against most Candida spp → Fungistatic against Aspergillus ``` 2.) MOA: inhibit the synthesis of glucan in the cell wall

Question 40

Echinocandins: Agents available?

Answer 40

􏰀 Caspofungin 􏰀 Micafungin 􏰀 Anidulafungin

Question 41

Echinocandins: 1. ) Formulations available? 2. ) Additional information? ( 3 things)

Answer 41

1.) IV formulations only for all 3 agents 2.) -Extensive distribution into tissues -Minimal CSF penetration → not for pts with CNS infections -97-99% protein bound

Question 42

Echinocandins: 1. ) Half life? 2. ) Side effects/Monitoring?

Answer 42

1.) Extensive half life: → once daily dosing 2. ) - Well tolerated-low adverse event rate - No renal adjustments required

Question 43

Caspofungin: Facts? ( 3 things)

Answer 43

-CYP inducers reduce dose→ so you need to increase dose ( 70mg/day) -Cyclosporine may increase AUC by 35% -Reduces tacrolimus levels by 20% → Tacrolimus is an immunosuppressant used in patients post transplant

Question 44

Micafungin: Facts? (2 things)

Answer 44

- Increases concentration of sirolimus → Sirolimus=prevent organ transplant rejection and to treat a rare lung disease called lymphangioleiomyomatosis. - Increases AUC and Cmax of nifedipine → nifedipine= DHP: Calcium channel blocker- used for Hypertension b/c it has a stronger reduction on systemic vascular resistance

Question 45

Flucytosine: 1.) Indication? 2.)MOA:?

Answer 45

1.) Indication: 􏰀 Candida spp. ( except C. krusei) 􏰀 Cryptococcus neoformans 􏰀 Aspergillus spp. 2.) MOA: Converted to 5-florouracil by susceptible fungi

Question 46

Flucytosine: 1. ) How do you administer this drug? 2. ) Is this drug given as monotherapy or in combination with something else?

Answer 46

1.) Administer over 15min and w/ food to limit n/v 2.)Usually not administered as a single agent! → bc of resistance → Has demonstrated synergy w/ AmB

Question 47

Flucytosine: 1. ) Bioavailability? 2. ) CNS penetration?

Answer 47

1. ) Bio- availability: - 80-90% orally bioavailable 2.) 74% CNS penetration

Question 48

Flucytosine: 1.) DDI's?

Answer 48

1. ) DDI's: | - Avoid with other nephrotoxic and bone marrow suppressive drugs

Question 49

Flucytosine: What side effects can this drug cause?

Answer 49

􏰀 N/V/D 􏰀 Bone marrow suppression ( dose dependent) 􏰀 Enterocolitis 􏰀 Hepatotoxicity

Question 50

Flucytosine: Monitoring?

Answer 50

-CBC, SCr, LFTs -Serum levels ( especially in pts w/ rapidly changing renal function) → Needs to be renally adjusted

Question 51

What allylamine agents are available?

Answer 51

``` *Always Touch Naked Butt* Amorolfine Terbinafine Naftifine Butenafine ```