Term
|
Definition
• Lipophilic rod-like
molecule produced
by Streptomyces
nodosus
• Gold standard for
antifungal therapy |
|
|
Term
| Amphotericin Mechanism of Action |
|
Definition
• Inserts into the fungal
cytoplasmic membrane
• Binds to sterols such as
ergosterol, which increases
membrane permeability
• Low drug concentration, K
channel activity is increased
• High drug concentrations
form pores, 40 nm to 105
nm, in the cell membrane |
|
|
Term
| Amphotericin Spectrum of Activity |
|
Definition
• Widest spectrum of activity of all the
antifungals
• Onset of action is rapid; not dependent on
organism’s growth rate
• Resistance is rare
- Due to the presence of altered membrane
sterols
- Candida species
• Candida albicans
• Candida (Torulopsis) glabrata
• Candida parapsilosis
• Candida tropicalis
• Candida krusei
• Candida lusitaniae—variable activity
- Aspergillus spp.
• Aspergillus fumigatus
• Aspergillus niger
• Aspergillus flavus
• Aspergillus terreus is amphotericin resistant!
• Cryptococcus neoformans
• Mucorales (Mucor spp., Rhizopus spp.)
• Histoplasma capsulatum
• Coccidioides immitis |
|
|
Term
|
Definition
• Nephrotoxicity
• Azotemia due to dose-dependent decrease in
the GFR
• Vasoconstrictive effect on the afferent renal
arterioles
• Expect Cr to rise to 2–3 mg/dL with use
• Permanent loss of renal function is rare
• GFR returns to baseline following cessation of therapy
- Infusion related
• Fever/rigors (“shake and bake”)
• Decreased incidence following multiple doses
• Premedicate with acetaminophen and
diphenhydramine
• Questionable efficacy however
• Treat rigors with low dose meperidine
- Nausea/vomiting
- Anemia (long-term administration) |
|
|
Term
Amphotericin Nephrotoxicity
• Exacerbated by: |
|
Definition
• Concomitant use of nephrotoxic agents
• Cyclosporine, tacrolimus, aminoglycosides
• Pre-existing renal insufficiency
• Intravascular volume depletion; hypotension |
|
|
Term
Amphotericin Nephrotoxicity
• Ameliorated by: |
|
Definition
Saline loading (NS before/after)
• Increased infusion time
(24 hours vs. six hours) |
|
|
Term
Amphotericin Nephrotoxicity
• Causes |
|
Definition
renal tubular acidosis with
significant wasting of K+, Mg++, and
HCO3-
• Need to monitor K+, Mg++
• Replete aggressively despite decreased GFR |
|
|
Term
|
Definition
• Three preparations available
- ABLC
- AmBisome
• Less nephrotoxic
• No evidence of improved
efficacy over conventional
amphotericin B
• Much more costly than the
cost of conventional
amphotericin B
(i.e., non-liposomal formulation
-inc cns penetration |
|
|
Term
|
Definition
| L Amph has fewer side effects |
|
|
Term
|
Definition
Work by inhibiting the C14 alpha demethylation
of lanosterol
- Reduces concentration of ergosterol
• Ketoconazole
- No longer used for systemic fungal infections
• Fluconazole
• Itraconazole
- Use now superseded by voriconazole
• Voriconazole
• Posaconazole
• Isavuconazole |
|
|
Term
Triazoles
• Mechanism of action: |
|
Definition
• Inhibits lanosterol
C14-α demethylase,
which is an enzyme
necessary in ergosterol
biosynthesis
• Ergosterol is a
component in fungal
cell membranes
• Ergosterol depletion
leads to fungal cell lysis |
|
|
Term
| Fluconazole Spectrum of Activity |
|
Definition
- Candida spp.
• Candida albicans
• Candida parapsilosis
• Candida tropicalis
• Candida lusitaniae
- C. (Torulopsis) glabrata
• Resistance is likely
- C. krusei
• Innately resistant to fluconazole
• Cryptococcus neoformans
- Useful in maintenance therapy of
cryptococcus meningitis
• Histoplasma
- Not drug of choice
• Coccidioides immitis
• No activity against Aspergillus spp. |
|
|
Term
Side Effects
• Elevation in LFTs (10%)
• Extremely high doses (>800 mg) can
cause N/V
• Chronic therapy can cause alopecia |
|
Definition
|
|
Term
Fluconazole
• Drug-drug interactions |
|
Definition
• Inhibitor of CYP3A4
• Phenytoin: increases phenytoin levels by up to 75%
• Rifampin: decreases fluconazole levels by 23%
• Tacrolimus: increases levels significantly
• Cyclosporine: increases levels significantly
• Sirolimus: increases levels significantly
• Midazolam: increases midazolam levels by 30%
• Warfarin: increases INR by 39% |
|
|
Term
| Voriconazole Spectrum of Activity |
|
Definition
- Candida species
• C. albicans
• C. tropicalis
• C. paropsilosis
• C. krusei
• C. glabrata
- Improved activity, but cross-resistance
with fluconazole-resistant strains has
been seen
• Aspergillus species
• Excellent anti-aspergillus activity
• More effective in treatment of invasive
aspergillosis than amphotericin B
- Voriconazole response rate: 52.8%
- Amphotericin B response rate: 31.6%
(Herbrecht et al. NEJM 2002;347:408–15)
• Fusarium spp.
• Not active against Mucorales
(Mucor spp., Rhizopus spp.) |
|
|
Term
• Therapeutic drug monitoring (TDM) needed to ensure
clinical success
• Trough drug level (goal is 1 to 5 ug/mL) |
|
Definition
|
|
Term
Side Effects
• Elevated LFTs (10–20%)
• Transient ocular changes
- Blurred vision, changes in color vision
- Occurs early in therapy, then resolves
• Rash
• Drug-drug interactions
- Extensive list due to multiple P450
isoenzymes affected: 3A4, 2C19, 2C9
• Periostosis due to fluoride toxicity |
|
Definition
|
|
Term
• Use superseded by voriconazole for invasive
aspergillus infections
- Voriconazole is more active and better bioavailability
• No benefit over fluconazole for candidal infections |
|
Definition
|
|
Term
• Used for treatment of histoplasmosis
infections
• Use oral cyclodextrin solution, not
capsules
• Greatly improved bioavailability
• Absorption not pH-dependent |
|
Definition
|
|
Term
| Posaconazole Spectrum of Activity |
|
Definition
• Candida spp.
- Similar to voriconazole
• Aspergillus
- Similar to voriconazole, but lack of
randomized controlled trial against
voriconazole or amphotericin B for treatment
of Aspergillosis
• Mucorales?
- Dependent on species |
|
|
Term
Posaconazole
• Drug interactions |
|
Definition
|
|
Term
| Isavuconazole Spectrum of Activity |
|
Definition
• Candida spp.
- Similar to voriconazole
• Aspergillus spp.
- Similar to voriconazole and posaconazole
• Mucorales |
|
|
Term
• FDA approved to treat invasive
aspergillosis non-inferiority trial
• 30-day mortality for invasive fungal
disease |
|
Definition
| Isavuconazole comparative to Voriconazole |
|
|
Term
• FDA approval for treatment of mucorales
infections based on response in case
series of 37 patients
• Success rate was 31.4% |
|
Definition
|
|
Term
• Inhibits β (1,3)-D-glucan synthase
• Weakens fungal cell wall |
|
Definition
|
|
Term
| Echinocandins Spectrum of Activity |
|
Definition
- Candida spp.
• C. albicans
• C. glabrata
• C. tropicalis
• C. krusei
• C. parapsilosis
• C. lusitaniae
- Aspergillus spp.
• Aspergillus
fumigatus
• Aspegillus flavus
• Aspergillus niger
• Intrinsic resistance seen in:
- Candida parapsilosis
- Candida guilliermondii
• Due to alterations in FKS 1 and 2 which
affects binding of the echinocandin
• Acquired resistance seen in other Candida
species following prolonged exposure
• Not active against:
- Mucorales
- Cryptococcus neoformans
- Histoplasma capsulatum
- Fusarium spp. |
|
|
Term
• Clinical utility
• Candidal infections
• C. glabrata candidemia
• Azole-resistant Candida esophagiti
• Invasive aspergillus infections
• Role is unclear, as no head-to-head comparison
versus voriconazole
• Role of combination therapy has not been studied
rigorously |
|
Definition
|
|
Term
Side Effects
• Histamine reaction with infusion
• Pre-treat with diphenhydramine
• Drug-drug interactions
• Caspofungin
• Cyclosporine, tacrolimus, rifampin
• Not seen with micafungin or anidulafungin
• CNS penetration is poor |
|
Definition
|
|
Term
| Which antifungal agent has the broadest spectrum of activity? |
|
Definition
|
|
Term
| Which medication requires a high fat meal to optimize absorption? |
|
Definition
|
|
Term
|
Definition
| caspofungin, anidulafungin, micafungin |
|
|
