Azole Antifungals:

Background:

1. Antifungals began with Amphotericin B in 1958

a. The standard for >40 years, despite the infusion related reactions
i. Issue was nephrotoxic
2. Fluconazole!
a. Came around in 1990
b. GREAT oral bioavailability
c. Food considerations
i. _________________
d. Predictive pharmacokinetics
i. _________________
e. Lower risk of drug interactions
f. Lower risk of toxicity
g. Excellent activity against Candida
h. Quickly became one of the most widely prescribed antifungal agents
i. For mucosal and systemic yeast infections
a) Lacking effects:
a. Opportunistic molds
i. Aspergillus
ii. Mucorales
iii. Fusarium
b. Some Candida species
i. _________________
ii. _________________

3. Itraconazole
o Came around in 1992
o Also demonstrate excellent activity against Candida
o Partial solution to fluconazole issues
▪ Spectrum also includes endemic fungi such as histoplasmosis
o Issues:
▪ Erratic absorption (capsules)
▪ GI side effects (solution formulation)

Even though these had all those benefits, the coverage that is missed created a need for broader
spectrum!
1. Voriconazole
a. 2002
o Like fluconazole - GREAT oral bioavailability
o Broad spectrum, retained anti candida activity, added activity against filamentous fungi
o Shown to be more effective than amphotericin B in aspergillosis
o Useful in fusariosis
 2. Posaconazole
a. 2006
b. Oral
c. Broad spectrum with added activity against filamentous fungi while retaining anti
candida activity
d. Activity against
i. Aspergillus and Fusarium species
ii. Also Mucorales (rare infection)
3. Isavuconazole
a. Similar spectrum to voriconazole and posaconazole
b. Similar broad activity with more favorable pharmacologic properties, allowing for
improved bioavailability, more predictable drug levels, and fewer drug interactions

• Fluconazole
o Indications:
▪ Candidiasis, invasive candidiasis, mucosal Cryptococcosis Prophylaxis,
Candidiasis
o Notes:
ii. CrCl < 50: _________________

i.Not Active:
• C krusei
• Aspergillus spp
• Fusarium spp
• Scedosporium spp
• Mucorales
i.Can treat, but MICs are higher: C glabrata, C guilliermondii, and C rugosa with
o Dosing:
▪ IV: 400-800 mg/day or 100-200mg/day
▪ Oral: 400-800mg/day or 100-200mg/day
• Itraconazole
o Indications:
▪ Blastomycosis Candidiasis, mucosal Coccidioidomycosis, Histoplasmosis,
Onychomycosis, Paracoccidioidomycosis, Sporotrichosis
▪ Second line: Aspergillosis
o Notes:
o Higher MICs for C glabrata and C krusei
o Dosing:
▪ Oral 200mg 1-3x/day
o Other:
o _________________

• Voriconazole
o Indications: Anti-Candida like fluconazole, but adds C glabrata
▪ Aspergillosis, Candidiasis – invasive, Candidiasis – mucosal, Fusariosis,
Scedosporiosis
o Notes:
iii. CrCl <50: _________________
iv. _________________: Consider 50% reduction

o Dosing:
▪ IV: 6mg/kg for 2 doses, then 4mg/kg Q12h
▪ Oral: 400mg BID for 2 doses, then 200mg Q12h
o Other notes
o _________________

• Posaconazole
o Indications:
▪ Candidiasis – mucosal, Prophylaxis, invasive fungal infection
▪ Potent activity against Aspergillus spp
o Notes:
o GFR <50: _________________
o With higher MICs for C krusei, C glabrata, and C guilliermondii
o Dosing:
▪ IV: 300mg/day
▪ Oral: Suspension – 800mg/day divided, Tablet – 300mgBID for 2 doses, then
300mg/day
• Isavuconazole
o Indications:
▪ Aspergillosis, Mucormycosis
▪ Most Candida spp, including C glabrata and C krusei
o Notes:
▪ Severe hepatic impairment: caution
o Dosing:
▪ IV: 372mg IV Q8h for 6 doses, then 372 mg/day
▪ Oral: 372mg Q8h for 6 doses, then 372 mg/day
Other Notes:
• Azoles act as substrates and inhibitors of CYP enzyme
• _________________
• Givens the drug-drug interactions for azoles
o Some interactions:
▪ Antiarrhythmics, antipsychotics, immunosuppressants, migraine medications,
antibiotics, anticoagulants, antidepressants, antiepileptics, antiretrovirals,
chemotherapy, antihypertensives, lipid-lowering agents, narcotics, sedatives,
hormonal therapies, diabetic medications
Azoles
• The original azole drugs – ketoconazole, miconazole have significant toxicity
o The newer triazole
o (fluconazole, itraconazole, Posaconazole, voriconazole, isavuconazole) have
improved safety panel
o Available as topical preparations for the treatment of vaginal candidiasis or cutaneous
fungal infection
▪ Ketoconazole, miconazole, clotrimazole, butoconazole, tioconazole,
terconazole

Antifungal pharmacology
1. Azole drugs are able to absorbed through GI mucosa
o Varies by azole
2. Fungi
a. Are similar to mammal cells and offer a few areas that we target
3. Azoles target
a. Ergosterol
4. Problem!
a. Not entirely selective to fungi
i. Human CYP also inhibited (Drug interactions)
Resistance
• Most common:
o Mutation in the azole binding pocket
o Overexpression of MDR1 efflux pumps (expel fluconazole)
▪ There is also CDR1 and CDR2 efflux pumps: (these are triphosphate
depending AND EXPEL ALL TRIAZOLES! (cross resistance)
• Candida krusei
o Impaired binding in fluconazole
• Candida glabrata
o Multidrug efflux pumps

Pharmacokinetic considerations:
• Echinocandins and Amphotericin B must be given IV → bad oral bioavailability
o AZOLES FIX THIS!
▪ But the degree of absorption varies from one drug to the next
Pharmacology
• The pharmacokinetic characteristics of the individual azole drugs are distinct due to variation in:
• _________________
• _________________
• _________________

• Fluconazole
o Unique – due to low molecular weight and high aqueous solubility
o Currently 2 oral formulations
o _________________
o _________________

o And an IV formulation

How often is fluconazole dosed?

o Penetrations
▪ Most body tissues
• CNS
• Eye
• High concentration in urine – 66%-76%
o Primarily renally cleared
o Unlike most triazoles
▪ Fluconazole is not extensively metabolized by the liver
• Itraconazole
o Available in 2 oral preparations
▪ Capsule
• Absorption is about 55%
• _________________
• _________________
• _________________

▪ Oral solution with hydroxypropyl-B-cyclodextrin

• Absorption is about 80%
• Usually preferred due to improved absorption

o Serum levels and therapeutic response

▪ Oral candidiasis or prophylaxis for fungal infections
• levels > 0.5 μg/mL is suggested
▪ Invasive fungal infections
• Concentrations of 1-2 μg/mL
o HIGHLY PROTEIN BOUND – 99%

Checkpoint: Knowing that it is highly protein bound, what make it different than fluconazole and
voriconazole?
o Unique pharmacokinetic observation
▪ Accumulation of Itraconazole in the skin and nail tissues
o Metabolism
▪ 3A4 to the active hydroxyitraconazole and several inactive metabolites
 ▪ Not useful in lower urinary tract infections
▪ Hepatic metabolism
• Dose reduction recommended in hepatic impairment
• Voriconazole
o Formulations
▪ Oral tablet, oral suspension
• Good bioavailability ~90%
• IV formulation
o Serum levels
▪ Can vary widely among patients
▪ Voriconazole is metabolized by CYP enzymes, primarily 2C19
▪ Studies have shown that concentrations from 1-2 μg/mL show success
• Levels >6 μg/mL are linked to adverse reactions
• _________________
• _________________
• _________________

▪ Hepatically metabolized – 2C9, 2C19, and 3A4

• Dose should be decreased in hepatic impairment
o Minimal active drug is secreted in the urine
▪ Not useful for treating fugal UTIs

• Posaconazole
o Trials have shown
▪ Posaconazole to be as effective or more effective for preventing invasive fungal
infections when compared to fluconazole or Itraconazole
o NOT RECOMMENDED AS FIRST LINE
▪ MAY BE USED AS AN ALTERNATIVE
o Also approved as an alternative for aspergillosis treatment

• Isavuconazole
o Approved for the treatment of invasive aspergillosis and invasive mucormycosis
▪ Approval was based on a large study that compared Voriconazole and
isavuconazole
• Isavuconazole showed better outcomes for all cause mortality and
treatment success was similar and noniferiority seen

Pharmacodynamic Considerations:

• So the usual dose of Fluconazole: 6mg/kg daily

o MICs >16 would be hard to reach
▪ Instead of intermediate → categorized as _________________
o Candida with MICs > 64μg/ml would require doses of 1600mg/day
▪ These would be classified as_________________
• Fluconazole MIC breakpoints:
o C albicans ,C parapsilosis, C tropicalis
▪ < 2μg/ml – susceptible
 ▪ 4μg/ml - susceptible dose dependent
▪ >8 μg/ml – resistant
o C glabrata
▪ < 32μg/ml – susceptible dose dependent
▪ < 64μg/ml – resistant

Therapeutic Monitoring of Antifungals

• Some antifungals have variability in the blood, so they are difficult to predict the concentration
based on the dose

Checkpoint: Knowing what I have said about the kinetics, which Azoles do you think have
recommendations for getting levels?
• Itraconazole, Voriconazole, and Posaconazole
Why?
• Erratic absorption (itra and posa)
• Hepatic clearance (vori)
• Drug interactions

Itraconazole, Posaconazole, Voriconazole: Candida, aspergillus, Cryptococcus, and coccidiodes immitis

• Successful treatment: 6 μg/ mL (determined by bioassay)
• Itraconazole toxicity reported
• >5 μg/mL(high performance liquid assay) or 17 μg/ mL (from bioassay)
• _________________
• Voriconazole
• Lots can cause variation!
• Age, dose, liver function, drug interactions, genetic polymorphisms affecting
2C19
• Common Side effects
• Photopsia (eye floaters or flashes)
• Liver function test abnormalities
• Encephalopathy, hallucinations, hypoglycemia, electrolyte disturbances,
pneumonitis (less common)
• Posaconazole
• Recommended prophylaxis trough concentrations _________________
• Treatment concentrations for mold infection _________________
• The frequency and timing of serum sampling for triazoles is not well established
o Sampling of troughs should be at steady state (5-7 days)
Toxicities of Antifungal Agents
• Need to know the dose limiting toxicity AND the long term risks
o Azoles = hepatotoxicity (dose limiting SE)
o Longer term
▪ Drug interactions, organ dysfunction, cutaneous reactions and malignancies
• Oral Itraconazole
o Nausea and GI disturbances associated with the cyclodextrin excipient
▪ Making it hard to tolerate in prolonged treatment
o Also (mostly in older patients)
▪ HTN, hypokalemia, and edema

• Rash is reported with all antifungal classes

o Voriconazole has been associated with
▪ Retinoid-like phototoxic (sensitive to light)
▪ Reactions that present with cheilitis (chapped lips)
▪ Erythema (skin redness)
▪ Occasional blistering
▪ However, it has been linked to squamous cell carcinoma and melanoma

Other Pearls:
• All azoles except isavuconazole
o Cause QT prolongation

• Isavuconazole
o Is associated with QT shortening and is contraindicated in patients with familial short QT
syndrome

• Pregnancy
o The azoles are contraindicated in pregnancy due to an established link to birth defects

Sources:
• Nett JE, Andes DR. Antifungal Agents: Spectrum of Activity, Pharmacology, and Clinical
Indications. Infect Dis Clin North Am. 2016;30(1):51-83. doi:10.1016/j.idc.2015.10.012
• Lewis RE. Current concepts in antifungal pharmacology. Mayo Clin Proc. 2011;86(8):805-
817. doi:10.4065/mcp.2011.0247
• Thompson GR 3rd, Cadena J, Patterson TF. Overview of antifungal agents. Clin Chest
Med. 2009;30(2):203-v. doi:10.1016/j.ccm.2009.02.001