Antifungal Agents

Polyenes—Amphotericin B
 MOA: Binds to
ergosterol within the
fungal cell membrane
resulting in
depolarization of the
membrane and the
formation of pores. The
pores permit leakage of
intracellular contents.
Exhibits concentration
dependent killing.
 Zygomycetes +
Scedosporidium +
Polyenes—Amphotericin B

Tricosporon +
– Holes: C. lusitanae, Fusarium, Tricosporon, Scedosporium

Fusarium +
Histoplasma +++
Blastomyces ++
Coccidioides +++
– Active against most molds and yeasts

Cryptococcus +++
Aspergillus ++
– Broad spectrum antifungal

lusitanae --
parapsilosis +++
Spectrum of Activity

Candida
tropicalis +++
krusei +++
glabrata ++
albicans +++

 Polyenes—Amphotericin B
 Resistance
– Susceptibility testing methods have not been
standardized
– Development of resistance in a previously
susceptible species is uncommon
– Mechanisms of Resistance
 Reductions in ergosterol biosynthesis
 Synthesis of alternative sterols that lessen the
ability of amphotericin B to interact with the fungal
membrane
 Polyenes—Amphotericin B
 Isolated from Streptococcus nodosus in 1955
 Amphotericin B is “amphoteric”
– Soluble in both basic and acidic environments
– Insoluble in water
Formulations
 Amphotericin B deoxycholate
– Fungizone
 Amphotericin B colloidal dispersion
– Amphotec, Amphocil
 Amphotericin B lipid complex
– Abelect
 Liposomal amphotericin B
– Ambisome
 Amphotericin B deoxycholate
 Distributes quickly out of blood and into liver and other
organs and slowly re-enters circulation
– Long terminal-phase half-life (15 days)
 Penetrates poorly into CNS, saliva, bronchial secretions,
pancreas, muscle, and bone
 Disadvantages
– Glomerular Nephrotoxicity—Dose-dependent decrease in GFR because
of vasoconstrictive effect on afferent renal arterioles
 Permanent loss of renal function is related to the total cumulative dose
– Tubular Nephrotoxicity—K, Mg+, and bicarbonate wasting
– Decreased erythropoietin production
– Acute Reactions—chills, fevers, tachypnea
 Support
– Fluids
– Potassium replacement
– Avoid concurrent nephrotoxic agents
– Premed with acetaminophen, diphenhydramine or hydrocortisone
– Meperidine for rigors
 Dose: 0.3 to 1 mg/kg once daily
 Amphotericin B Colloidal Dispersion
(Amphotec)
 Cholesterol sulfate in equimolar amounts to
amphotericin B
 Similar kinetics to amphotericin B
deoxycholate
 Acute infusion related reactions similar to
amphotericin B deoxycholate
 Reduced rates of nephrotoxicity compared
to amphotericin B deoxycholate
 Dose
– 3 to 4 mg/kg once daily
 Amphotericin B Lipid Complex
(Abelcet)
 Equimolar concentrations of amphotericin and lipid
 Distributed into tissues more rapidly than
amphotericin B deoxycholate
– Lower Cmax and smaller AUC than amphotericin
deoxycholate
– Highest levels achieved in spleen, liver, and lungs
– Delivers drug into the lung more rapidly than Ambisome
– Lowest levels in lymph nodes, kidneys, heart, and brain
 Reduced frequency and severity of infusion related
reactions
 Reduced rate of nephrotoxicity
 Dose
– 5 mg/kg once daily
 Liposomal Amphotericin B
(AmBisome)
 Liposomal product
– One molecule of amphotericin B per 9 molecules of lipid
 Distribution
– Higher Cmax and larger AUC
– Higher concentrations achieved in liver, lung, and spleen
– Lower concentrations in kidneys, brain, lymph nodes and heart
– May achieve higher brain concentrations compared to other
amphotericin B formulations
 Reduced frequency and severity of infusion related
reactions
 Reduced rate of nephrotoxicity
 Dose
– 3 to 6 mg/kg once daily
 Flucytosine
 MOA
– Converted by cytosine
deaminase into 5-fluorouracil
which is then converted through
a series of steps to 5-
fluorouridine triphosphate and
incorporated into fungal RNA
leading to miscoding
– Also converted by a series of
Fluorinated pyrimidine
steps to 5-fluorodeoxyuridine
monophosphate which is a
noncompetitive inhibitor of
thymidylate synthase, interfering
with DNA synthesis
 Flucytosine
 Spectrum of Activity
– Active against
 Candida species except C. krusei
 Cryptococcus neoformans
 Aspergillus species
– Synergy with amphotericin B has been demonstrated
 The altered permeability of the fungal cell membrane produced by
amphotericin allows enhanced uptake of flucytosine
 Mechanisms of Resistance
– Loss of cytosine permease that permits flucytosine to cross the
fungal cell membrane
– Loss of any of the enzymes required to produce the active forms
that interfere with DNA synthesis

Resistance occurs frequently and rapidly when flucytosine is given as

monotherapy
Combination therapy is necessary
 Flucytosine
 Half-life
– 2 to 5 hours in normal renal function
– 85 hours in patients with anuria
 Distributes into tissues, CSF, and body fluids
 Toxicities
– Bone marrow suppression (dose dependent)
– Hepatotoxicity (dose dependent)
– Enterocolitis
Toxicities occur more commonly in patients with renal impairment
 Dose
– Administered orally (available in 250 and 500 mg capsules)
– 100 to 150 mg/kg/day in 4 divided doses
– Dose adjust for creatinine clearance
 Flucytosine concentrations should be monitored especially
in patients with changing renal function
 Contraindicated in pregnancy
 Azoles—Ketoconazole
 Ketoconazole, a lipophilic antifungal agent
Has both oral and topical formulations to be used in the
treatment of systemic mycoses, dermetophytosis and
cutaneous candidiasis.

Spectrum activity
High Low Resistance

Candida spp. Scedosporium Aspergillus spp.

ploroficans
Histoplasma S. apiospermum Fusarium spp.
capsulatum
Zygomycetes
 Ketoconazole
 MOA: Inhibits 14-α-sterol demethylase,
which is a microsomal CYP450 enzyme.
This enzyme is responsible for conversion
of lanosterol to ergosterol, the major
sterol of most fungal cell membranes
 Triazoles
 MOA: Inhibits 14-α-
sterol demethylase,
which is a microsomal
CYP450 enzyme. This
enzyme is responsible
for conversion of
lanosterol to
ergosterol, the major
sterol of most fungal
cell membranes
 Triazoles—Spectrum of Activity
Fluconazole Itraconazole Voriconazole Posaconazole

C. albicans +++ ++ +++ +++

C. glabrata + + ++ ++
C. krusei -- + +++ ++
C. tropicalis +++ ++ +++ +++
C. parapsilosis +++ ++ +++ +++
C. lusitanae ++ ++ +++ +++
Aspergillus -- ++ +++ +++
Cryptococcus +++ +++ +++ +++
Coccidioides +++ +++ +++ +++
Blastomyces ++ +++ ++ +++
Histoplasma + +++ ++ +++
Fusarium -- -- ++ ++
Scedosporium -- +/- + +/-
Zygomycetes - - - ++
 Triazoles
Fluconazole Itraconazole Voriconazole
Absorption IV and PO PO IV and PO
Good Capsule ≠ Suspension 90% oral
bioavailability Capsules best absorbed bioavailability
with food.
Suspension best
absorbed on empty
stomach.
Distribution Wide. Low urinary levels Wide.
Good CNS Poor CNS Good CNS
penetration penetration penetration

Metabolism Hepatic/Renal Hepatic CYP 2C9, 2C19,

3A4
Saturable
metabolism

Elimination 80% excreted Excreted in feces Minimal renal

unchanged in the excretion
urine
 Triazoles—Fluconazole
 Dose
– 100 to 400 mg daily
– Renal impairment:
 CrCl >50 ml/min, give full dose
 CrCl<50 ml/min, give 50% of dose
 Dialysis: replace full dose after each session
 Drug Interactions
– Minor inhibitor of CYP 3A4
– Moderate inhibitor of CYP 2C9
 Warfarin, phenytoin, cyclosporine, tacrolimus,
rifampin/rifabutin, sulfonylureas
 Adverse Drug Reactions
– Well tolerated
– Nausea
– Elevated LFTs
UNC Hospital Formulary
 Triazoles—Itraconazole
 Dose
– 200 to 400 mg/day (capsules)
 doses exceeding 200 mg/day are given in 2 divided doses
 Loading dose: 200 mg 3 times daily can be given for the first 3 days
– Oral solution is 60% more bioavailable than the capsules
 Drug Interactions
– Major substrate of CYP 3A4
– Strong inhibitor of CYP 3A4
– Many Drug Interactions
 Adverse Drug Reactions
– Contraindicated in patients with CHF due to negative inotropic effects
– QT prolongation, torsades de pointes, ventricular tachycardia, cardiac
arrest in the setting of drug interactions
– Hepatotoxicity
– Rash
– Hypokalemia
– Nausea and vomiting
 Triazoles—Voriconazole
Drug Interactions
Major substrate of CYP 2CD and 2C19
Minor substrate of CYP 3A4
Weak inhibitor of CYP 2C9 and 2C19
Moderate inhibitor of CYP 3A4

 Common Adverse Effects  Serious Adverse Events

– Peripheral edema – Stevens-Johnson Syndrome
– Rash (6%)
– Liver failure
– N/V/D
– Hepatotoxicity – Anaphylaxis
– Headache – Renal failure
– Visual disturbance (30%) – QTc prolongation
– Fever
 Echinocandins
MOA
Irreversibly inhibits B-1,3 –D glucan synthase, the
enzyme complex that forms glucan polymers in the
fungal cell wall. Glucan polymers are responsible for
providing rigidity to the cell wall. Disruption of B-
1,3-D glucan synthesis leads to reduced cell wall
integrity, cell rupture, and cell death.
 Gallagher JC, et al. Expert Rev Anti-Infect Ther 2004;2:253-268

Zygomycetes -
Scedosporidium -
Echinocandins—Spectrum of

Fusarium -
Histoplasma --
Blastomyces ++
Coccidioides ++
Activity

Cryptococcus --
Aspergillus +++
guilliermondii +
lusitanae +++
parapsilosis +
Candida tropicalis +++
krusei +++
glabrata +++
albicans +++
 Echinocandins—Adverse Effects
 Generally well tolerated
 GI side effects, Hypokalemia
 Abnormal liver function tests
 Caspofungin
– Tends to have higher frequency of liver
related laboratory abnormalities
– Higher frequency of infusion related pain and
phlebitis