Antifungal Agents

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Antifungal Agents

• Lindsay Mayer Daniels, PharmD
• August 15, 2008

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PolyenesAmphotericin 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.

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PolyenesAmphotericin B

• Spectrum of Activity
• Broad spectrum antifungal
• Active against most molds and yeasts
• Holes C. lusitanae, Fusarium, Tricosporon,
  Scedosporium

Candida Candida Candida Candida Candida Candida Aspergillus Cryptococcus Coccidioides Blastomyces Histoplasma Fusarium Tricosporon Scedosporidium Zygomycetes
albicans glabrata krusei tropicalis parapsilosis lusitanae Aspergillus Cryptococcus Coccidioides Blastomyces Histoplasma Fusarium Tricosporon Scedosporidium Zygomycetes
--
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PolyenesAmphotericin B

• Resistance
• Susceptibility testing methods have not been
  standardized
• Development of resistance in a previously
  susceptible species is uncommon
• Proposed mechanisms
• Reductions in ergosterol biosynthesis
• Synthesis of alternative sterols that lessen the
  ability of amphotericin B to interact with the
  fungal membrane

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PolyenesAmphotericin 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

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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 NephrotoxicityDose-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 NephrotoxicityK, Mg, and bicarbonate
  wasting
• Decreased erythropoietin production
• Acute Reactionschills, fevers, tachypnea
• Support
• Fluids
• K and Mag replacement
• Avoid concurrent nephrotoxic agents
• Premed with acetaminophen, diphenhydramine or
  hydrocortisone
• Meperidine for rigors
• Dose 0.3 to 1 mg/kg once daily

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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

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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

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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

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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 steps to
  5-fluorodeoxyuridine monophosphate which is a
  noncompetitive inhibitor of thymidylate synthase,
  interfering with DNA synthesis

Fluorinated pyrimidine
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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
• Always use combination therapy

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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

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AzolesKetoconazole

• Uses
• Used in U.S. as an alternative
• Non-albicans candidiasis
• Blastomycosis
• Histoplasmosis
• Not for immunocompromised hosts due to high
  failure rate
• Coccidioidomycosis
• Not for meningitis or for severely ill
• Paracoccidioidomycosis
• Inactive against non-albicans candida and
  Aspergillus
• Needs acidic environment for absorption
• Only available PO
• Distributes into epidermis, synovial fluid,
  saliva, and lungs. Poor distribution into CSF
  and eye.
• Dose
• 200 to 400 mg once daily
• Decrease dose for severe liver failure

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ImidazolesKetoconazole

• Adverse Effects
• GI distress (17-43)
• Rash (4-10)
• Increased transaminases (2-10)
• Hepatitis (1 in 10,000)
• Can be fatal if drug is not DCd
• Usually occurs within first 4 months of treatment
• Dose-dependent inhibition of synthesis of
  testosterone (5-21 of patients will have
  symptoms such as impotence or gynecomastia)
• Menstrual Irregularities (16 of women)
• Alopecia (8)
• Dose-related decrease in cortisol synthesis
• Hypermineralocorticoid state
• Can cause HTN in patients on long-term high dose
  ketoconazole
• Teratogenic in animals

• Drug Interactions
• Antacids, H2 blockers, proton pump inhibitors,
  sucralfate
• Decreases absorption of ketoconazole
• Rifampin decreases ketoconazole concentrations by
  33
• CYP inhibition
• Cyclosporine levels increased
• Warfarin
• Phenytoin
• Methylprednisolone
• Isoniazid
• Terfenadine
• Astemizole
• Cisapride

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Triazoles

• MOA Inhibits 14-a-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

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TriazolesSpectrum 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 - - -
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TriazolesADME
Fluconazole Itraconazole Voriconazole Posaconazole
Absorption IV and PO Good bioavailability PO Capsule ? Suspension Capsules best absorbed with food. Suspension best absorbed on empty stomach. 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
Elimination 80 excreted unchanged in the urine Excreted in feces Minimal renal excretion Minimal renal excretion of parent compound 66 excreted in feces
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TriazolesFluconazole

• Dose
• 100 to 800 mg daily
• Renal impairment
• CrCl gt50 ml/min, give full dose
• CrCllt50 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

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TriazolesItraconazole

• 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

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TriazolesVoriconazole

• Dose
• IV
• 6 mg/kg IV for 2 doses, then 3 to 4 mg/kg IV
  every 12 hours
• PO
• gt 40 kg200-300 mg PO every 12 hours
• lt 40 kg100-150 mg PO every 12 hours
• Cirrhosis
• IV
• 6 mg /kg IV for 2 doses, then 2 mg/kg IV every
  12 hours
• PO
• gt 40 kg100 mg PO every 12 hours
• lt 40 kg 50 mg PO every 12 hours
• Renal impairment
• if CrCllt50 ml/min, use oral formulation to avoid
  accumulation of cyclodextrin solubilizer

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TriazolesVoriconazole
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
Dose Adjustments Efavirenz Phenytoin Cyclosporine
Warfarin Tacrolimus

• Common Adverse Effects
• Peripheral edema
• Rash (6)
• N/V/D
• Hepatotoxicity
• Headache
• Visual disturbance (30)
• Fever

• Serious Adverse Events
• Stevens-Johnson Syndrome
• Liver failure
• Anaphylaxis
• Renal failure
• QTc prolongation

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TriazolesPosaconazole

• 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

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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.

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EchinocandinsSpectrum of Activity
Candida Candida Candida Candida Candida Candida Candida Aspergillus Cryptococcus Coccidioides Blastomyces Histoplasma Fusarium Scedosporidium Zygomycetes
albicans glabrata krusei tropicalis parapsilosis lusitanae guilliermondii Aspergillus Cryptococcus Coccidioides Blastomyces Histoplasma Fusarium Scedosporidium Zygomycetes
-- -- - - -
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Echinocandins
  Caspofungin Micafungin Anidulafungin
Absorption Not orally absorbed. IV only Not orally absorbed. IV only Not orally absorbed. IV only
Distribution Extensive into the tissues, minimal CNS penetration Extensive into the tissues, minimal CNS penetration Extensive into the tissues, minimal CNS penetration
Metabolism spontaneous degradation, hydrolysis and N-acetylation spontaneous degradation, hydrolysis and N-acetylation Chemical degradated Not hepatically metabolized
Elimination Limited urinary excretion. Not dialyzable Limited urinary excretion. Not dialyzable 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
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EchinocandinDrug 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

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EchinocandinsAdverse 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

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References

• Gallagher JC, et al. Expert Rev Anti-Infect Ther
  20042253-268
• UNC Hospital Formulary
• Patel R. Antifungal Agents. Part I. Amphotericin
  B Preparations and Flucytosine. Mayo Clin Proc
  1998731205-1225
• Terrel CL. Antifungal Agents. Part II. The
  Azoles. Mayo Clin Proc 19997478-100.
• Mehta J. Do variations in molecular structure
  affect the clinical efficacy and safety of lipid
  based amphotericin B preparations? Leuk Res.
  199721183-188.
• 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 200423256-270.
• Capelletty D et al. The echinocandins.
  Pharmacotherapy 200727369-388.
• Spanakis EK et al. New agents for the treatment
  of fungal infections clinical efficacy and gaps
  in coverage. Clin Infect Dis 2006431060-8.
• Rex JH, Stevens DA. Systemic Antifungal Agents.
  In Mandell GL, Bennet JE, Dolin R, eds. Mandell,
  Douglas, and Bennetts Principles and Practice
  of Infectious Diseases. Vol 1. 6th ed. New York,
  NY McGraw-Hill2005502.