Antifungals Flashcards
1
Q
Infectious Disease
Approach
A
2
Q
Kingdom Myceteae
A
Yeast ⇒ unicellular, replicate by budding
Mold ⇒ multicellular hyphae
3
Q
Polyenes
Overview
A
2 common agents:
Nystatin & Amphotericin B
MOA:
Bind ergosterol in fungal cell membrane ⇒ cell death
4
Q
Polyenes
Adverse Effects
A
Considerable toxicity:
- Nephrotoxicity
-
Electrolyte wasting
- K+, Mg2+, etc lost in urine
-
Infusion related reactions
- Common occurance
- Anything from fevers to rigors
5
Q
Polyenes
Pharmacokinetics
A
- Poorly absorbed
-
Highly distributed
- Minimally detectable in CNS
- Metabolism and elimination unknown
6
Q
Polyenes
Pharmacodynamics
A
Concentration-dependent
7
Q
Amphotericin B (AmB)
Overview
A
- Polyene antifungal
-
Broad spectrum
- Candida spp.
- Except C. lusitaniae
- Cryptococcus neoformans
- Dimorphic fungi
- Many molds
- Candida spp.
- Considerable nephrotoxicity
-
Amphotericin B deoxycholate (AmBd)
- First polyene ⇒ called conventional AmB
- Worse toxicity
- Cheapest
8
Q
Amphotericin B
Nephrotoxicity
A
-
Damages distal tubule
- Leads to Na+, K+, and Mg2+ wasting
-
Damages afferent arterioles
- Reduces glomerular perfusion and kidney function
9
Q
Amphotericin B
Lipid Formulations
(LFABs)
A
-
3 formulations
-
Amphotericin B Colloidal Dispersion (ABCD)
- No longer made
- Amphotericin B Lipid Complex (ABLC)
-
Liposomal amphotericin B (LAmB)
- Best option, most protective of host
-
Amphotericin B Colloidal Dispersion (ABCD)
- Efficacy differences ⇒ need bigger doses
- Safety profiles
- Nephrotoxicity ⇒ ABCD = ABLC > LAmB
- Infusion reactions ⇒ ACBD >> ABLC > LAmB
10
Q
Nystatin
A
- Polyene antifungal
- Broad spectrum
- Only given topically due to toxicity
11
Q
Echinocandins
MOA
A
⊗ β-1,3-glucan synthetase ⇒ ↓ β-1,3-glucan production ⇒ cell wall stability
(Many molds and dimorphic don’t have β-1,3-glucan in their cell walls = not effective)
12
Q
Echinocandins
Spectrum
A
-
Strong in vitro activity against clinical Candida spp.
- Weaker against C. parapsilosis
- Active against Aspergillus spp.
- Ineffective for Cryptococcus & many molds
- Efficacy unknown for many mycoses
13
Q
Echinocandins
Pharmacokinetics
A
All given IV.
- Poor bioavailability
- Well distributed
- Variable metabolism
-
Not eliminated renally
- Not useful for fungal UTI’s
14
Q
Echinocandins
Pharmacodynamics
A
Concentration-dependent
All fungicidal against yeast
All pseudo-static against molds (abnormal growth morphology)
15
Q
Echinocandins
Adverse Effects
A
- Mild hepatotoxicity
-
Infusion-releated reactions
- More Vancomycin-like
-
Phlebitis
- Give through central venous line to minimize
16
Q
Echinocandins
Medications
A
17
Q
Azoles
MAO
A
⊗ fungal cytochrome P450 (14α-demethylase) ⇒ ↓ ergosterol formation
(Ergosterol is not present in human cell membranes)
18
Q
Azoles
Spectrum
A
Drug of choice for many fungal infections.
Variable antifungal spectrum:
- Flucanazole ineffective against some C. glabrata, C. krusei, Aspergillus spp., molds
- Itraconazole is effective against Aspergillus
- New agents have extended spectrum
19
Q
Azoles
Issues
A
⊗ human cytochrome P450s ⇒ many adverse effects
- Drug interactions
- Fluconazole resistance
- Used for prophylaxis
20
Q
Azoles
Adverse Reactions
A
-
Hepatotoxicity
- Worse w/ Voriconazole
- Best w/ Fluconazole
- Rash
21
Q
Azoles
Pharmacokinetics
A
Can be given PO.
- Absorption variable between agents
- Widely distributed including CNS
- All have some hepatic metabolism
-
Flucanzole mostly excreted renally
- Can be used for UTIs
22
Q
Azoles
Pharmacodynamics
A
Time-dependent
Fungicidal against molds
Fungistatic against yeasts
23
Q
Fluconazole
Indications
A
Available as IV, tablets, and oral suspensions
(100% bioavailability PO ⇒ same dose as IV)
-
Activity
-
Yeasts including many Candida and Cryptococcus
- Exceptions:
- C. kruseii ⇒ “cruise past it”
- C. glabrata ⇒ “glides past it”
- Exceptions:
- Some dimorphic fungi
- No anti-mold activity
-
Yeasts including many Candida and Cryptococcus
-
Uses:
- Treatment of many forms of candidiasis
- Prophylaxis of candidiasis
- Treatment of some dimorphic fungal infections
24
Q
Fluconazole
Adverse Effects
A
-
Hepatotoxicity
- Least toxic d/t renal elimination
- Rash
-
Drug interactions
- Fewest b/c it does not ⊗ CYP450-3A4
25
Itraconazole
Indications
**Available as capsules and oral solution.**
* Activity:
* **Yeasts** including Candida and Cryptococcus
* **Aspergillus**
* **Many dematiaceous molds**
* **Dimorphic fungi**
* Utility:
* Dimorphic fungal infections
* Onychomycosis
* Some mold and yeast infections
26
Itraconazole
Adverse Effects
* Absorption issues
* Capsules are very poorly absorbed
* Oral solution better but suspension agent can cause **diarrhea** ⇒ poor tolerance/compliance
* Hepatotoxicity
* Rash
* **Widening of QT interval**
* Worse of the Azoles
* **⊖ inotrope** ⇒ exacerbate CHF
* **Drug interactions**
* Does ⊗ CYP450-3A4 ⇒ lots of interactions
27
Voriconazole
Indications
**Available as IV, tablets, and oral suspension.**
Muct better absorption than Itraconazole.
* Activity:
* **Yeasts** including Candida and Cryptococcus
* **Molds** including _Aspergillus_, Fusarium, Scedosporium, dematiaceous molds, endemic fungi
* Utility:
* **Invasive aspergillosis** and other mold infections ⇒ drug of choice
* Invasive candidiasis
* Equally as effective as Fluconazole but more poorly tolerated, not drug of choice
* Esophageal candidiasis
* Febrile neutropenia?
28
Voriconazole
Pharmacokinetics
* Well-absorped
* **Hepatically metabolized**
* **Non-linear elimination**
* ****Pharmacokinetics and elimination are not dose proportional
* ↑ dose ⇒ ↓ clearance
* **SBECD of IV form is renally eliminated**
* Cyclodextrin part of drug
* Accumulates in renal failure
* **High intra- and inter- patient variability**
* High concentrations ⇒ toxicity
* Low concentrations ⇒ failure
* Must monitor dosing
29
Voriconazole
Adverse Effects
* **Visual effects** ⇒ 40-50% of pts
* Chromatic aboritions
* **Visual hallucinations**
* **Hepatotoxicity**
* Higher than other drugs in the class
* Usually just see ↑ total bilirubin w/ minimal change in AST/ALT
* Rash
* **Drug interactions**
* Does ⊗ CYP450-3A4 ⇒ lots of interactions
30
Posaconazole
Indications
**Available as IV, tablet, or oral suspension.**
* Activity:
* **Yeasts** including Candida and Cryptococcus
* **Molds** including Aspergillus and _Zygomycetes_
* Few antifungals active against Zygomycetes
* Utility:
* **Approved for prophylaxis of fungal infections**
* Mold infections
31
Posaconazole
Formulations & Pharmacokinetics
Available as IV, tablet, or oral suspension.
* **Suspension requires high-fat meal or acidic beverage**
* Largely not used anymore
* **Oral tablet ⇒ delayed release**
* IV form recently approved
32
Posaconazole
Adverse Effects
Better than Voriconazole.
Worse than Fluconazole.
* Hepatotoxicity
* Rash
* Drug interactions
33
Isavuconazole
Indications
* Activity:
* **Yeasts** including Candida and Cryptococcus
* **Molds** including Aspergillus and _Mucormycetes_
* **Dimorphic fungi**
* Utility:
* **Approved for treatment of aspergillosis and mucormycosis**
* Voriconazole is drug of choice for aspergillosis but is not active against mucormycosis
34
Isavuconazole
Pharmacokinetics
* **Given as prodrug isavuconazonium sulfate**
* **Long half-life ~ 130 hrs**
* Give loading dose to get to therapeutic level
35
Isavuconazole
Adverse Effects
* **Hepatotoxicity**
* Less than voriconazole
* Rash
* **Drug interactions**
* Less than other mold-active azoles
36
Ketoconazole
* Poor oral absorption
* **Used topically**
* Oral formulation exists but don't use it systemically
37
Topical Azoles
* Medications:
* Clotrimazole
* Econazole
* Miconazole
* Oxiconazole
* Sulconazole
* Terconazole
* Tioconazole
* Adverse effects ⇒ dermatologic
38
5-Flucytosine (5-FC)
MOA
**Antimetabolite**
* Deaminated within fungals cells ⇒ 5-fluorouracil
* **5-fluorouracil replaces uracil ⇒ ⊗ RNA production & DNA synthesis**
"5-FU for fungi"
39
5-Flucytosine
Pharmacokinetics
* High bioavailability
* **Widely distributed including CNS**
* **Renally excreted**
* Dose adjustment in renal dysfunction
* Pharmacokinetic monitoring available
* Trough concentrations: 20-25 mcg/mL
* Dose: 12.5-37.5 mg/kg q6h
40
5-Flucytosine
Indications
* Activity:
* **Candida species**
* **Cryptococcus neoformans**
* Less active against C. krusei
* **Some activity against Aspergillus and other molds**
* Utility:
* **Combo therapy for cryptococcal meingitis**
* ****Main use
* 5-FC w/ AmB is a good combo
* Rarely used for candidiasis
41
5-Flucytosine
Adverse Effects
* **Bone marrow suppression**
* Peak dose-related
* **GI intolerance**
* Hepatotoxicity
* Rash
42
Systemic Antifungals
Spectrum
43
Terbinafine
MOA
Allyamine antifungal
## Footnote
**⊗ squalene epoxidase ⇒ ⊗ ergosterol synthesis**
44
Terbinafine
Indications
Available PO and topically.
* Activity:
* **Mainly for dermatophytes**
* e.g. Trychophyton
* Active against Candida & Aspergillus
* Not used clinically
* Utility:
* **Onychomycosis**
45
Terbinafine
Pharmacokinetics
Available PO or topically.
* 40% bioavailability d/t 1st pass effect
* **Concentrates in nails, fat, and skin**
* **Metabolized in liver**
* **Metabolites renally excreted**
* **Non-linear elimination**
* T½ 12 hrs → 200-400 hrs w/ repeated dosing
46
Terbinafine
Adverse Effects
* Hepatotoxicity
* Neutropenia
* Steven-Johnson syndrome
47
Griseofulvin
MOA
⊗ fungal mitosis via interaction w/ microtubules
48
Griseofulvin
Pharmacokinetics
Given PO
Prolonged half-life
49
Griseofulvin
Indications & Adverse Effects
* Active against dermatophytes
* Used in treatment of onychomycosis
* Not preferred
* Adverse effects
* CNS
* Mainly headaches
50
Candida Susceptibility
Antifungal activity is species dependent.
