Azoles Flashcards
Azoles
Work by inhibiting fungal cytochrome P450- decreasing ergosterol production
This will cause drug interactions- most can be dealt with by dose adjustment; adjustment needs to be readjusted when the interactor is completed
Many different agents with variable spectrums and toxicity profiles
MOA
All azoles inhibit fungal CYP P450 14-alpha demethylase, inhibiting the conversion of lanosterol into ergosterol (which is a component of the fungal cell membrane)
Fluconazole
Introduced in 1990
Highly bioavailable
Oral and IV; oral conversion is simple
Highly active against many Candida species
Low incidence of serious adverse reactions
Shift toward non-albicans species has affected its use
Fluconazole Spectrum
Good C. albicans C. tropicalis C. parapsilosis C. lusitaniae Cryp. neoformans Coccidioides immitis
Moderate
C. glabrata (can be susceptible, dose dependent, or resistant)
Poor
Molds
Many dimorphic fungi
C. krusei
Fluconazole Adverse Effects
Generally well tolerated
Can cause hepatotoxicity or rash
Has lower risk for serious drug interactions compared with other azoles, but interactions still occur
QTc prolongation possible
Fluconazole Dosing Issues
Doses for systemic fungal infections may be escalated (especially C. glabrata infections)
Adjust dose with regard to renal function; drug eliminated through urine
Vulvovaginal candidiasis require only one time dose of 150mg of fluconazole
Fluconazole Important Facts
Poorly active against all C. krusei and some C. glabrata
If using for glabrata, best to check susceptibility and give 800mg/day after a loading dose
If lab does not do testing, consider an alternate (like echinocandin)
Often given as prophylaxis against Candida infections in susceptible populations (like ICU patients or some with cancer)
If patient was receiving it and now has yeast in blood, try echinocandin instead (may have fluconazole resistant Candida)
Had high bioavailability (excellent therapy to transition to as patients tolerate oral)
Before committing to definitive course of therapy, test patient’s isolate
Fluconazole Good For
Drug of choice for many infections (like invasive and noninvasive candidiasis and cryptococcal disease
Also used for some dimorphic fungi (like coccidioidomycosis)
Itraconazole
Broader spectrum azole
PK issues have impaired its greater use
Has Aspergillus and other mold species activity
Was once commonly used as step down therapy in aspergillosis; this use has declined due to voriconazole availability
Itraconazole Spectrum
Good C. albicans C. tropicalis C. parapsilosis C. lusitaniae Cryp. neoformans Aspergillus species Many dimorphic fungi
Moderate
C. glabrata
C. krusei
Poor
Mucorales
Many other molds
Itraconazole Adverse Effects
Causes more concerns than fluconazole
Hepatotoxicity
Negative ionotrope; contraindicated in heart failure
Oral solution associated with diarrhea
Stronger inhibitor of CYP P450 enzymes
Long list of drug interactions
QTc prolongation
Itraconazole Important Facts
Capsules have lower bioavailability than oral solution; capsules less preferred for systemic fungal infections
Capsules should always be taken with a full meal
Solution should be taken on an empty stomach
Absorption can be lowered by agents that decrease gastric acidity (PPIs); take the drug with a soda
Because absorption is so erratic and unpredictable, concentrations often monitored
Consider checking a trough if taking for a serious fungal infection and/or long time
Was available in an IV form; discontinued; older books may still reference it- ignore
Itraconazole Good For
Drug of choice for some dimorphic fungi (like histoplasmosis)
Used to have larger role in management and prophylaxis of aspergillosis and other mold infections; largely replaced by voriconazole
Capsules also used for treatment of onychomycosis
Voriconazole
Significant improvement in treatment of mold
Broad spectrum like itraconazole; good activity against Candida and many molds
Well absorbed; available in both highly bioavailable oral formulations and an IV admixture
Superior to AmphoB deoxycholate for invasive aspergillosis- now the drug of choice
Limitations in highly variable PK and long term adverse effects
Voriconazole Spectrum
Good C. albicans C. lusitaniae C. parapsilosis C. tropicalis C. krusei Cryp. neoformans Aspergillus species Many other molds
Moderate
C. glabrata
C. albicans that are fluconazole resistant
Fusarium species
Poor
Mucorales
Voriconazole Adverse Effects
Shares the adverse effects of the azole class (hepatotoxicity, rash, drug interactions)
Also agent specific effects
Renal
IV comes in cyclodextrin solubilizer; accumulates in renal dysfunction; nephrotoxic but less so than than AmphoB
Consider risk/reward with renally insufficient patients
Visual
Seeing wavy lines or halos around bright lights are very common and dose related
Tend to go away with continued use
CNS
Visual and auditory hallucinations (distinct from the common visual effects above)
Not permanent
Tend to occur at higher levels (especially during peak concentration periods)
Dermatologic
Causes sun sensitivity; use sunscreen and avoid excess exposure
Has been used for durations (treatment and prophylaxis) far exceeding those in clinical trials
May be association with prolonged use and certain skin cancers; very important to counsel on reducing sun exposure while on the drug
Voriconazole Dosing Issues
Highly variable interpatient PK and non-linear elimination; hard to dose correctly
If on extended course, monitor drug levels (usually trough)
No official consensus; 2-5 mg/L considered to be in therapeutic window
Voriconazole Important Facts
Active against some fluconazole resistant strains of C. albicans but is less effective than against the susceptible strains (do a test); echinocandin is better option
Potent inhibitor and a substrate of the CYP P450 system
Rifampin is contraindicated
Calcineurin inhibitors (cyclosporine) require dose adjustments; many of the patients who require it are immunosuppressed so interactions are significant
IV form contains cyclodextrin vehicle; accumulates in renal dysfunction and may be nephrotoxic
Contraindicated with a CrCL < 50 mL/min
Oral forms avoid this issue
Eliminated hepatically; unlikely to be useful in candiduria
Voriconazole Good For
Drug of choice for invasive aspergillosis
Frequently used for other molds
Can be used for candidiasis
Fluconazole and echinocandins used more often
Sometimes used in empiric treatment of febrile neutropenia
Posaconazole
Analog of itraconazole; substantially more active against many fungi
Indicated only for prophylaxis of fungal infection patients and treatment of oropharyngeal candidiasis
First azole with good activity against Mucorales (is a difficult to treat order of molds that most antifungals don’t treat); isavuconazole also has activity
Posaconazole Spectrum
Good C. albicans C. lusitaniae C. parapsilosis C. tropicalis C. krusei Aspergillus species Mucorales Many other molds Dimorphic fungi
Moderate
Fusarium species
C. glabrata
Comparative clinical trial data is lacking for many of these fungi
Posaconazole Adverse Reactions
Well tolerated
Can cause hepatotoxicity, nausea, and rash
Similar ability to cause interactions as other azoles
Posaconazole Dosing Issues
Initially only available as oral suspension (big limitation)
Requires administration with food to increase absorption
High fat foods, nutritional supplements containing fat, and low pH beverages like soda increase absorption
Absorption is limited and variable
Recently a DR tablet released; achieves much higher and more reliable concentrations; cannot be crushed or chewed
IV form also available
Posaconazole Important Facts
Most common use has been in prophylaxis of fungal infections in high risk patients; many of these patients are taking immunosuppressants that interact with posaconazole
In vitro activity against Aspergillus is generally similar to voriconazole; due to lack of comparative clinical trial data, hesitant to use it first line even though it is better tolerated
Oral suspension: high fat meals and acidic beverages boost absorption substantially
PPIs lower absorption; giving with soda will not overcome this
Drug concentrations available
Use for patients with questionable absorption and treatment of invasive infections
Posaconazole Good For
Most commonly used as prophylaxis against fungal infections in susceptible hosts
Can also be used in mucormycosis, oropharyngeal candidiasis, and fungal infections refractory to other agents
Lack of clinical trial data limits its more widespread use
Isavuconazole
Newest agent
Similar to posaconazole
Has expanded spectrum (Candida, Aspergillus, Mucorales)
IV and oral
Interactions
Toxicity profile that is most concerning for hepatic effects
It’s FDA approval based on trials in invasive aspergillosis and mucormycosis (posaconazole lacks trial data in these two but has more extensive clinical use)
Isavuconazole Spectrum
Good Candida species Aspergillus species Mucorales Other molds Other dimorphic fungi
Moderate
C. glabrata
Poor
Fusarium
Isavuconazole Adverse Reactions
Hepatotoxicity similar to other azoles (somewhat less frequent than voriconazole)
Does not appear to prolong QT interval but can shorten it; does not seem to have clinical significance except in congenital short QT intervals
May be used in patients with prolonged QT intervals who would be at risk for arrhythmia with another azole
Isavuconazole Dosing Issues
Bioavailability of capsule is excellent; not affected by food or gastric acidity
Capsules are hard; not designed to be opened, crushed, or chewed; limits use of feeding tube or swallowing issues
Has very long half life
To attain therapeutic levels more rapidly, is extensive loading dose regimen
Every 8 hours for 6 doses (48 hours) then once daily maintenance
Supplied as prodrug (isavucazonium sulfate); hydrolyzed to isavuconazole after administration
Funky dosing
372mg of isavucazonium = 200mg of isavuconazole; leads to confusion
Isavuconazole Important Facts
Has in vitro activity against Candida similar to voriconazole and posaconazole
One study showed it not noninferior to capsofungin in invasive Candida infections; will not be given approval for invasive candidiasis
Posaconazole has approval for the less severe oropharyngeal candidiasis; has not been studied for invasive candidiasis
Voriconazole does have approval for invasive candidiasis; echinocandins may be more effective than AmphoB and fluconazole for this indication
For invasive candidiasis, use echinocandins (most effective) whenever possible or fluconazole (balance of efficacy and convenience)
It’s PK more predictable than voriconazole and possibly posaconazole; reassured by demonstrating adequate drug levels; currently fewer labs offer levels compared to voriconazole or posaconazole
Make sure correct dose and full loading given or patient will take a week to get to a subtherapeutic steady state
Not much experience with it yet but based on trial data, appears to be good option for invasive mold infections
