Anti-Fungal Agents in the Hospital Setting

Question 1

MOA of amphotericin B

Answer 1

• Binds to ergosterol in fungal cell membrane and INCREASE membrane permeability
  
  • INCREASE in membrane permeability will lead to cell lysis
• IRREVERSIBLE inhibition of chitin synthetase–> thus augmenting the membrane effect of the drug (Chitin is a cell-wall polysaccharide)

Question 2

MOA of triazoles

Answer 2

Inhibit 14-alpha-sterol demethylase, prevent ergosterol synthesis, and lead to the accumulation of 14-alpha-methylsterols (precursor of ergosterol)

Question 3

MOA of Echinocandins

Answer 3

Inhibit the formulation of glucans in the fungal cell wall

Question 4

What are some drug interactions of azoles?

Answer 4

• ALL azoles are inhibitors of CYP3A4 enzyme system
• Voriconazole and Fluconazole also inhibit CYP2C8/9 and CYP2C19
• Fluconazole is intermediate in inhibition, depending on dose
• Isavuconazole is more modest inhibitor of CYP3A4 compared to voriconazole and Posaconazole
• Azole metabolism ENHANCED by CYP450 INDUCERS (e.g., rifampin and phenytoin)
  
  • May require dose INCREASE

Question 5

What are the drug interactions of Echinocandins?

Answer 5

• Poor substrates for CYP3A4
• Caspofungin and tacrolimus
• Caspofungin and rifampin, phenytoin, dexamethasone requiring caspofungin dosage** INCREASES**
• Micafungin does NOT affect tacrolimus BUT INCREASES AUCs of sirolimus and nifedipine and DECREASES the clearance of cyclosporine

Question 6

What are the drug interactions of Amphotericin?

Answer 6

Synergistic nephrotoxicity

Question 7

What is the MOA of azoles?

Answer 7

Inhibit fungal cytochrome P450 14-alpha demethylase, inhibiting the conversion of lanosterol into ergosterol, which is a component of the fungal cell membrane

Question 8

What are the clinical pearls of azoles?

Answer 8

Most useful for invasive candidiasis, esp. with azole resistance, OR 3rd line for invasive aspergillosis (esp. when toxicity to other classes is observed)

Question 9

Mechanisms of azole resistance

Answer 9

• Reduced permeability of the fungal cell membrane to azoles
• Modification or overproduction of the target fungal enzymes (cytochrome P450, CYP) resulting in decreased binding of the azole to the target site of the CYP
• Alterations in sterol synthesis within organisms
• Activation of efflux pumps capable of actively pump azoles from the target pathogen

Question 10

T/F: Fluconazole has poor coverage for Candida krusei

Answer 10

T

Question 11

What is the pharmacokinetics of Fluconazole?

Answer 11

HIGH renal excretion with dose adjustment with impaired kidney function

Question 12

What is the metabolism of Voriconazole?

Answer 12

• Complex biotransformation-CYP2C19 (most), CYP3A4, CYP2C9
• Dose-dependent metabolism result in non-linear pharmacokinetics (presents PK drug monitoring due to unpredictable nature of plasma concentration vs. time profile)

Question 13

What are the side effects of Voriconazole?

Answer 13

• Uniquely associated with phototoxicity and skin cancer (long-term use)
• Reversible disturbance of vision (30%) usually during 1st week and resolve: altered color discrimination, blurred vision, bright spots, wavy lights, photophobia

Question 14

What is the Therapeutic Drug Monitoring of Voriconazole?

Answer 14

Target 1-2 mcg/mL for fungal prophylaxis, 2-5 mcg/mL for treatment
* Avoid > 5 mcg/mL due to visual hallucinations, halo light, other toxicities

Question 15

What is the spectrum of activity of Posaconazole?

Answer 15

• Broad spectrum of antifungal activity, including Aspergillus and Candida species and variable activity against the Mucorales

Question 16

What is the oral formulation of Posaconazole?

Answer 16

• Oral suspension administered 2-3 times a day WITH high fat meal/nutritional supplement
• Better product – delayed-release tablet for once daily after loading dose twice daily for one day
• NEW extended-release suspension – ideal for children – would provide better option than voriconazole

Question 17

What are the side effects of Cresemba (Isavuconazole)?

Answer 17

• Nausea
• Diarrhea
• Elevated LFTs

Question 18

What is the indication of Cresemba (Isavuconazole)?

Answer 18

• Alternative to voriconazole for invasive aspergillosis
• Has a more favorable and predictable drug interaction profile
• Studies show that this agent can DECREASE the QTc

Question 19

What are the Echinocandins?

Answer 19

• Caspofungin
• Micafungin
• Anidulafungin

Question 20

What is the more detailed MOA of Echinocandins?

Answer 20

Concentration-dependent, non-competitive inhibitors of beta-1, 3-D-glucan synthase (an essential component of the cell wall of susceptible filamentous fungi that is absent in mammalian cells)

Question 21

What is the administration of Echnocandins?

Answer 21

• Degraded primarily by the liver (but also in the adrenals and spleen) by hydrolysis and N-acetylation
• **Caspofungin – adjusted dose in severe hepatic dysfunction **

Question 22

What are the adverse effects of Echinocandins?

Answer 22

• Mild histamine-mediated infusion-related reactions
• Rare hepatotoxicity
• Some drug interactions (cyclosporine with caspofungin, less than for the azoles)

Question 23

What are the indications of Echinocandins?

Answer 23

Useful for invasive candidiasis, esp. with azole resistance, OR 3rd line for invasive aspergillosis (esp. when toxicity to other classes)

Question 24

Brexafemme

Answer 24

• Terpenoids (New class)
• Inhibit beta-1,3-D-glucan synthase (same target as echinocandins)
• May work vs echinocandin-resistant Candida isolates
  
  • May have some activity vs Aspergillus

Question 25

What is the administration of Brexafemme?

Answer 25

• PO but presently ONLY approved for vulvovaginal candidiasis
  
  • For mild/moderate infection in immunocompetent patients who are not pregnant, CANNOT take fluconazole or have refractory/resistant infection to fluconazole
• May affect CYP3A4 as substrate, P450 inhibitor

Question 26

What are the adverse effects of Brexafemme?

Answer 26

Gastrointestinal: Abdominal pain (11%), diarrhea (17%), nausea (12%)

Question 27

What is the pharmacokinetics of Amphotericin B?

Answer 27

• POOR oral absorption – note the size of the molecule (VERY BIG)!
• Minimal amounts enter the aqueous humor, bile, pericardial fluid, pleural fluid, and synovial fluid
• CNS penetration is poor
• Protein binding is poor
• Protein binding, plasma: 90%
• Excretion: Urine (only 2-5%); 40% eliminated over 7-day period; may be detected in urine for at least 7 weeks after discontinued

Question 28

What consist of the new formulation of Amphotericin B?

Answer 28

• Liposomal Amphotericin
• Distribute into tissues more rapidly
• Highest levels in spleen, lungs, liver
• Lowest levels in kidney, lymph nodes, brain, heart
• Reduced rate and severity of infusion reactions
• Reduced rates of nephrotoxicity

Question 29

What is a serious adverse effect of Amphotericin B?

Answer 29

Nephrotoxicity
* Dose dependent renal damage with
- Azotemia
- Polyuria
- Distal, renal tubular acidosis
- Hyposthenuria (inability to concentrate urine)
- Nephrocalcinosis (i.e., calcification of the kidney)
* Hypokalemia (K+ decrease)–> induces rhabdomyolysis–> CPK increase (indicating muscle damage) –> Hypomagnesemia (Mg+2 decrease)
* Renal damage/nephrotoxicity worse in Na+ depletion
- ** Reduced by “sodium loading” using BOLUSES of normal saline BEFORE and AFTER AmB infusion **

Question 30

What are some other side effects of Amphotericin B?

Answer 30

• Hypokalemia, hypomagnesemia
• Renal tubular acidosis
• Renal insufficiency
• Tachypnea
• Hypotension

Question 31

What should monitor for in side effects of Amphotericin B?

Answer 31

• BUN and serum creatinine QOD, then 1-2x/week
• Electrolytes (especially potassium and magnesium