Transcript Antifungal Agents

Antifungal Agents
Lindsay Mayer, PharmD
October 26, 2007
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.
Polyenes—Amphotericin B
Spectrum of Activity
– Broad spectrum antifungal
– Active against most molds and yeasts
– Holes: C. lusitanae, Fusarium, Tricosporon,

Scedosporium
Histoplasma
Fusarium
Tricosporon
Scedosporidium
Zygomycetes
++
+++
+
+
+
+
--
Blastomyces
lusitanae
+++
+++
parapsilosis
+++
Coccidioides
tropicalis
+++
+++
krusei
++
Cryptococcus
glabrata
+++
++
albicans
Aspergillus
Candida
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

Fluorinated pyrimidine
MOA
– Converted by cytosine
deaminase into 5-fluorouracil
which is then converted through
a series of steps to 5fluorouridine triphosphate and
incorporated into fungal RNA
leading to miscoding
– Also converted by a series of
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
Triazoles

MOA: Inhibits 14-αsterol 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—ADME
Fluconazole
Absorption
IV and PO
Good
bioavailability
Itraconazole
PO
Capsule ≠ Suspension
Capsules best
absorbed with food.
Suspension best
absorbed on empty
stomach.
Voriconazole
Posaconazole
IV and PO
90% oral
bioavailability
PO--Absorption
enhanced with
high fat meal
Distribution Wide.
Good CNS
penetration
Low urinary levels
Poor CNS
penetration
Wide.
Good CNS
penetration
Widely
distributed into
tissues
Metabolism Hepatic/Renal
Hepatic
CYP 2C9, 2C19,
3A4
Saturable
metabolism
Not a substrate of
or metabolized by
P450, but it is an
Inhibitor of 3A4
Minimal renal
excretion
Minimal renal
excretion of parent
compound
66% excreted in
feces
Elimination 80% excreted
Excreted in feces
unchanged in the
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

Dose
Triazoles—Itraconazole
– 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

Dose
– IV
 6 mg/kg IV for 2 doses, then 3 to 4 mg/kg IV every 12 hours
– PO
 > 40 kg—200-300 mg PO every 12 hours
 < 40 kg—100-150 mg PO every 12 hours

Cirrhosis:
– IV
 6 mg /kg IV for 2 doses, then 2 mg/kg IV every 12 hours
– PO
 > 40 kg—100 mg PO every 12 hours
 < 40 kg— 50 mg PO every 12 hours

Renal impairment:
 if CrCl<50 ml/min, use oral formulation to avoid
accumulation of cyclodextrin solubilizer
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
– Peripheral edema
– Rash (6%)
– N/V/D
– Hepatotoxicity
– Headache
– Visual disturbance (30%)
– Fever

Dose Adjustments
Efavirenz
Phenytoin
Cyclosporine
Warfarin
Tacrolimus
Serious Adverse Events
– Stevens-Johnson Syndrome
– Liver failure
– Anaphylaxis
– Renal failure
– QTc prolongation
Triazoles—Posaconazole

Dosing (only available PO)
– Prophylaxis of invasive Aspergillus and Candida species
 200 mg 3 times/day
– Treatment of oropharyngeal candidiasis
 100 mg twice daily for 1 day, then 100 mg once daily for 13 days
– Treatment or refractory oropharyngeal candidiasis
 400 mg twice daily
– Treatment of refractory invasive fungal infections (unlabeled
use)
 800 mg/day in divided doses

Drug Interactions
– Moderate inhibitor of CYP3A4

Adverse Reactions
– Hepatotoxicity
– QTc prolongation
– GI: Diarrhea
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 B1,3-D glucan synthesis leads to reduced cell wall
integrity, cell rupture, and cell death.
Echinocandins—Spectrum of
Activity
Histoplasma
Fusarium
Scedosporidium
Zygomycetes
--
-
-
-
+
++
guilliermondii
+++
Blastomyces
lusitanae
+
++
parapsilosis
+++
Coccidioides
tropicalis
+++
--
krusei
+++
Cryptococcus
glabrata
+++
+++
albicans
Aspergillus
Candida
Gallagher JC, et al. Expert Rev Anti-Infect Ther 2004;2:253-268
Echinocandins
Caspofungin
Micafungin
Anidulafungin
Absorption
Not orally absorbed. IV only
Distribution
Extensive into the tissues, minimal CNS penetration
Metabolism
spontaneous degradation,
hydrolysis and N-acetylation
Elimination
Chemical degradated
Not hepatically
metabolized
Limited urinary excretion. Not dialyzable
Half-life
9-23 hours
11-21 hours
26.5 hours
Dose
70 mg IV on day
1, then 50 mg IV
daily thereafter
100 mg IV
once daily
200 mg IV on day 1,
then 100 mg IV
daily thereafter
Dose
Adjustment
Child-Pugh 7-9
70 mg IV on day 1,
then 35 mg IV daily
thereafter
CYP inducers
70 mg IV daily
None
None
Echinocandin—Drug Interactions

Caspofungin
– Not an inducer or inhibitor of CYP enzymes
– CYP inducers (i.e. phenytoin, rifampin, carbamazepine)
 Reduced caspofungin levels
– Increase caspofungin dose
– Cyclosporine
 Increases AUC of caspofungin
 Hepatotoxicity
– Avoid or monitor LFTs
– Tacrolimus
 Reduced tacrolimus levels by 20%
– Monitor levels of tacrolimus

Micafungin
– Minor substrate and weak inhibitor of CYP3A4
– Nifedipine
 Increased AUC (18%) and Cmax (42%) of nifedipine
– Sirolimus
 Increased concentration of sirolimus

Anidulafungin
– No clinically significant interactions
Cappelletty et al. Pharmacotherapy 2007;27:369-88
Echinocandins—Adverse Effects
Generally well tolerated
 Phlebitis, 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
References
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Gallagher JC, et al. Expert Rev Anti-Infect Ther 2004;2:253-268
UNC Hospital Formulary
Patel R. Antifungal Agents. Part I. Amphotericin B Preparations and
Flucytosine. Mayo Clin Proc 1998;73:1205-1225
Terrel CL. Antifungal Agents. Part II. The Azoles. Mayo Clin Proc 1999;74:78100.
Mehta J. Do variations in molecular structure affect the clinical efficacy and
safety of lipid based amphotericin B preparations? Leuk Res. 1997;21:183-188.
Groll AH et al. Penetration of lipid formulations of amphotericin B into cerebral
fluid and brain tissue. 37th ICAAC, 1997. Abstract A90.
Gallagher JC et al. Recent advances in antifungal pharmacotherapy for invasive
fungal infections. Expert Rev. Anti-infect. Ther 2004; 2: 253-268.
Groll AH et al. Antifungal Agents: In vitro susceptibility testing,
pharmacodynamics, and prospects for combination therapy. Eur J Clin Microbiol
Infect Dis 2004;23:256-270.
Capelletty D et al. The echinocandins. Pharmacotherapy 2007;27:369-388.
Spanakis EK et al. New agents for the treatment of fungal infections: clinical
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Rex JH, Stevens DA. Systemic Antifungal Agents. In: Mandell GL, Bennet JE,
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