Azole Questions Flashcards
How do azoles work?
Inhibit fungal cytochrome P450
-decreases ergosterol production
What idea needs to be remembered about drug interactions?
- most drug interactions can be successfully dealt with by dose adjustment but not all
- any dose adjustments made while a patient is receiving an interacting drug needs to be readjusted when therapy with the interactor is finished
When was fluconazole introduced?
1990
What are the benefits of fluconazole?
- highly bioavailable
- available in both IV and PO (converting from IV to oral is simple)
- highly active against many species of Candida
- low incidence of serious adverse reactions
What factor has affected the use of fluconazole?
Shift toward non-albicans species of Candida
What is the MOA of azoles?
Inhibit fungal cytochrome P450 14-alpha demethylase
-inhibits conversion of lanosterol into ergosterol (it is a component of the fungal cell membrane)
What organisms does fluconazole have GOOD activity against?
- Candida albicans
- Candida tropicalis
- Candida parapsilosis
- Candida lusitaniae
- Cryptococcus neoformans
- Coccidioides immitis
What organisms does fluconazole have MODERATE activity against?
- Candida glabrata
- can be:
- susceptible
- dose-dependent
- resistant
What organisms does fluconazole have POOR activity against?
- molds
- many dimorphic fungi
- Candida krusei
What are the adverse effects of fluconazole?
Generally well tolerated
Can cause
- hepatotoxicity
- rash
- QTc prolongation possible
What is fluconazole’s propensity for serious drug interactions compared to many other azoles?
Lower propensity for serious interactions
-interactions still occur
How does fluconazole dosing change for some systemic fungal infections?
May be escalated
-particularly for treatment of Candida glabrata infections
How is fluconazole eliminated?
Through the urine
-adjust dosing with regard to renal function
What is the dose for vulvovaginal candidiasis for fluconazole?
One time dose of 150mg
What organisms is fluconazole poorly active against?
- all Candida krusei
- some Candida glabrata
What are some factors to consider when treating Candida glabrata with fluconazole?
- best to check susceptibility (if lab does not do testing for fungi, consider an alternative such as echinocandin)
- give 800mg/day after a loading dose
When is fluconazole used as prophylaxis?
Often against Candida infections in susceptible patients
- ICU patients
- patients with some cancers
If patient was receiving fluconazole prophylaxis and now has yeast in the blood, what should be tried?
Patient may have fluconazole resistant Candida
-try echinocandin instead
As patient begins to tolerate oral therapy, what is an excellent therapy to transition to?
Fluconazole
-has high oral bioavailability
What is fluconazole good for?
Drug of choice for many susceptible fungal infections
- invasive and noninvasive candidiasis
- cryptococcal disease
Some dimorphic fungal infections
-coccidioidomycosis
Are all species of Candida fluconazole-susceptible?
No
-check patient’s isolate before committing to a definitive course of therapy
How does itraconazole compare to fluconazole?
Broader spectrum azole
Why doesn’t itraconazole have a bigger place in therapy?
PK issues
What activity does itraconazole have?
Against
- Aspergillus
- other mold species
What was itraconazole once commonly used for?
Step down therapy in aspergillosis
-use has declined because of voriconazole
What organisms does itraconazole have GOOD activity against?
- Candida albicans
- Candida tropicalis
- Candida parapsilosis
- Candida lusitaniae
- Cryptococcus neoformans
- Aspergillus species
- many dimorphic fungi
What organisms does itraconazole have MODERATE activity against?
- Candida glabrata
- Candida krusei
What organisms does itraconazole have POOR activity against?
- Mucorales
- many other molds
How does itraconazole’s adverse effect profile compare with fluconazole?
Causes more concerns
In what patients is itraconazole contraindicated?
Patients with heart failure
-negative ionotrope
What is the itraconazole oral solution associated with?
Diarrhea
What is the strength of itraconazole drug interaction compared with fluconazole?
Stronger inhibitor
-many drug interactions
What other adverse effects are associated with itraconazole?
- hepatotoxicity
- QTc prolongation
Which dosage form of itraconazole has worse bioavailability?
Capsules have lower bioavailability compared to solution
-less preferred for systemic fungal infections
How should itraconazole oral capsules be taken?
Always be taken with a full meal
How should itraconazole oral solution be taken?
Always on an empty stomach
How does pH affect itraconazole absorption?
Absorption can be lowered by agents that decrease gastric acidity
- such as PPIs
- try taking with a soda
Are itraconazole concentrations monitored?
Yes
-absorption is so erratic and unpredictable
Consider checking a trough concentration if
- taking for a serious fungal infection
- and/or a long time
Is itraconazole available as an IV formulation?
Not anymore
What is itraconazole good for?
Drug of choice for some dimorphic fungal infections
-ex: histoplasmosis
For what infections has voriconazole largely replaced itraconazole?
Management and prophylaxis of
- aspergillosis
- other mold infections
What are itraconazole capsules used for?
Treatment of onychomycosis
What did the introduction of voriconazole represent a significant improvement in?
Treatment of mold infections
How does voriconazole differ from itraconazole?
- well absorbed
- available in highly bioavailable oral formulations and IV admixture
What is voriconazole active against?
Broad spectrum antifungal
Good activity against
- Candida species
- many molds
How does voriconazole compare to amphotericin B deoxycholate?
Superior for invasive aspergillosis and now is the drug of choice
What are some limitations of voriconazole?
- highly variable PK
- long term adverse effects
What organisms does voriconazole have GOOD activity against?
- Candida albicans
- Candida lusitaniae
- Candida parapsilosis
- Candida tropicalis
- Candida krusei
- Cryptococcus neoformans
- Aspergillus species
- many other molds
What organisms does voriconazole have MODERATE activity against?
- Candida glabrata
- fluconazole-resistant Candida albicans
- Fusarium species
What organisms does voriconazole have POOR activity against?
Mucorales
What are common class adverse effects of azoles?
- hepatotoxicity
- rash
- drug interactions
What are the categories of adverse effects of voriconazole?
- renal
- visual effects
- CNS effects
- dermatologic
Why is voriconazole associated with nephrotoxicity?
The cyclodextrin solubilizer in IV voriconazole accumulates in renal dysfunction
- thought to be nephrotoxic
- almost certainly less toxic than amphotericin B
- risk/reward consideration in renally insufficient patients
Describe voriconazole visual effects.
-seeing wavy lines
or
- halos around bright lights
- very common
- dose-related
- tend to go away with continued use
Describe voriconazole CNS effects.
Sometimes experience visual and auditory hallucinations
- are distinct from the common visual effects
- not permanent
When do voriconazole CNS effects tend to occur?
At higher voriconazole levels
-especially during peak concentration periods
Describe voriconazole dermatologic effects.
Sun sensitivity
- use sunscreen
- avoid excessive sun exposure
Some studies suggest association between prolonged use and certain skin cancers
-reducing sun exposure is so important
Describe voriconazole PK.
- highly variable interpatient PK
- nonlinear elimination
- difficult to dose correctly
How is voriconazole monitored?
Serum drug concentrations
- usually a trough level
- no official consensus; (2-5 mg/L usually considered to be in the therapeutic window)
Is voriconazole active against fluconazole-resistant strains of C. albicans?
Against some
- less active than against fluconazole-susceptible strains
- consider susceptibility testing if you need to use it as oral option
- echinocandin is a better choice
Does voriconazole inhibit other drugs?
Potent inhibitor and substrate of P450
- long and varied drug interaction list
- some contraindicated (ex: rifampin)
- some require dose adjustments (calcineurin inhibitors: ex: cyclosporine)
- many patients who are immunosuppressed require voriconazole (be alert for drug interactions)
When is IV voriconazole contraindicated?
In patients with severe renal dysfunction
- (CrCL < 50 mL/min)
- IV form contains cyclodextrin (accumulates in renal dysfunction and is nephrotoxic)
- oral forms avoid this issue
How is voriconazole eliminated?
Hepatically
-unlikely to be useful in treatment of candiduria
What is voriconazole good for?
Drug of choice for
-invasive aspergillosis
Frequently used in treatment of infections caused by other molds
Can be used for candidiasis
-fluconazole and echinocandins more frequently used for these infections
Some clinicians use it for
-empiric treatment of febrile neutropenia
What are two important points to think about when using voriconazole?
- watch for drug interactions
- consider checking drug concentrations if using for extended course of therapy
What is posaconazole?
Analog of itraconazole
-substantially more active against many fungi
What is posaconazole indicated for?
Prophylaxis of
-fungal infections in high risk patients
Treatment of
-oropharyngeal candidiasis
What is the first azole with good activity against Mucorales?
Posaconazole
-Mucorales is a difficult to treat order of molds that most antifungals do not treat
What organisms does posaconazole have GOOD activity against?
- Candida albicans
- Candida lusitaniae
- Candida parapsilosis
- Candida tropicalis
- Candida krusei
- Aspergillus species
- Mucorales
- many other molds
- dimorphic fungi
What organisms does posaconazole have MODERATE activity against?
- Fusarium species
- C. glabrata
What is something to consider about posaconazole’s spectrum of activity?
Though it is active against these organisms, comparative clinical trial data are lacking for many of them
Describe posaconazole’s adverse reactions.
-seems to be well tolerated
Can cause
- hepatotoxicity
- nausea
- rash
How does posaconazole’s propensity to cause drug interactions compare with other azoles?
Similar
What was a key limitation to posaconazole’s use?
Initial availability only as oral suspension
-absorption is limited and variable even under the best circumstances
What is required to take with the posaconazole suspension?
Administration with food to increase absorption
- foods with high fat concentration
- nutritional supplements containing fat
- low-pH beverages like soda
What dosage forms of posaconazole exist?
- oral suspension
- delayed-release tablet
- IV
What are some facts about the posaconazole delayed-release tablet?
- achieves much higher and more reliable concentrations compared to the oral suspension
- cannot be crushed or chewed
What is a consideration with posaconazole prophylactic use?
Many of these patients are on immunosuppressants
- watch for drug interactions
- monitor drug concentrations
- same as for voriconazole
Why are clinicians hesitant to use posaconazole first line against Aspergillus?
In vitro activity against Aspergillus is generally similar to voriconazole and it is better tolerated but:
-lacks clinical trial data comparing it to voriconazole (or even amphotericin)
What is a consideration with the posaconazole oral suspension?
Issues with absorption
- high fat meals and acidic beverages boost absorption substantially (may be required for adequate absorption in some patients)
- proton pump inhibitors lower absorption (administering with soda will not overcome this factor)
When should posaconazole concentrations be monitored?
- patients with questionable absorption
- if used for treatment of invasive infections
What is posaconazole most commonly used for?
Prophylaxis against fungal infections in susceptible hosts
What can posaconazole be used for?
- mucormycosis
- oropharyngeal candidiasis
- fungal infections refractory to other agents
What is posaconazole’s major limitation to more widespread use?
Lack of clinical trial data
Which two azoles have very different dosing and administration with their oral formulations (capsules/tablets and suspension)?
- itraconazole
- posaconazole
What is the newest azole?
Isavuconazole
How is isavuconazole similar to posaconazole?
- expanded spectrum of activity (includes: Candida, Aspergillus, Mucorales)
- available as IV and oral formulations
- has P450-mediated drug interactions
- toxicity profile most concerning for hepatic effects
How is isavuconazole different than posaconazole?
- isavuconazole’s FDA approval based on clinical trials in invasive aspergillosis and mucormycosis (posaconazole lacks clinical trial data for these)
- posaconazole has more extensive clinical use
What organisms does isavuconazole have GOOD activity against?
- Candida species
- Aspergillus species
- Mucorales
- some other molds
- some dimorphic fungi
What organisms does isavuconazole have MODERATE activity against?
Candida glabrata
What organisms does isavuconazole have POOR activity against?
Fusarium species
How does isavuconazole hepatotoxicity compare with other azoles?
Similar level to other azoles is anticipated
-may be somewhat less frequent than with voriconazole
Other azoles prolong the QT interval. What effect does isavuconazole have?
Shortens it
- may affect patients with congenitally short QT intervals
- may allow for use in patients with prolonged QT intervals who would be at risk for arrhythmia if prescribed a different azole
Describe the bioavailability of isavuconazole’s oral formulation (capsule)?
Excellent
- not affected by food or gastric acidity
- capsules are hard
- not designed to be opened, crushed, or chewed (limits administration in patients with feeding tubes or swallowing issues)
What is isavuconazole’s half life?
Very long
-requires loading dose
Why does isavuconazole have a loading dose?
To attain therapeutic levels more rapidly (due to very long half)
Describe isavuconazole’s extensive loading dose regimen.
Administration every 8 hours for six doses (48 hours)
Then transition to a once daily maintenance regimen
How is isavuconazole supplied?
As a prodrug (isavucazonium sulfate)
-hydrolyzed to isavuconazole after administration
372mg of isavucazonium yields 200mg of isavuconazole
-leads to potential for confusion in ordering doses
How does isavuconazole’s in vitro activity against Candida species compare to voriconazole and posaconazole?
Similar
What type of candidiasis is posaconazole FDA approved for?
The less severe oropharyngeal candidiasis
-not studied in invasive candidiasis
What type of candidiasis is voriconazole FDA approved for?
Invasive candidiasis
- based on the results of a study comparing it to conventional amphotericin B followed by fluconazole
- echinocandins may be more effective than the above combination
How does isavuconazole compare to the echinocandins in invasive candidiasis?
Not noninferior
What drugs should be used for invasive candidiasis?
- echinocandins (most effective)
- fluconazole (balance of efficacy and convenience)
How does isavuconazole’s PK compare to voriconazole and possibly posaconazole?
More predictable
How do clinicians feel reassured when using azoles?
By demonstrating adequate serum drug levels
-fewer labs offer isavuconazole levels than voriconazole or posaconazole currently
What is isavuconazole good for?
Not extensive experience with it yet; trial data shows it to be a good option in
-invasive mold infections
What is an important fact to remember about isavuconazole?
Give the correct dose as well as full loading regimen
-otherwise will take a week to get to a subtherapeutic steady state
