Antifungal AgentsAntifungal Agents

Lindsay Mayer, PharmDLindsay Mayer, PharmD

October 26, 2007October 26, 2007

Polyenes—Amphotericin BPolyenes—Amphotericin B MOA: Binds to MOA: Binds to

ergosterol within the ergosterol within the fungal cell membrane fungal cell membrane resulting in resulting in depolarization of the depolarization of the membrane and the membrane and the formation of pores. formation of pores. The pores permit The pores permit leakage of leakage of intracellular contents. intracellular contents. Exhibits concentration Exhibits concentration dependent killing.dependent killing.

Polyenes—Amphotericin BPolyenes—Amphotericin B Spectrum of ActivitySpectrum of Activity

– Broad spectrum antifungalBroad spectrum antifungal– Active against most molds and yeastsActive against most molds and yeasts– Holes: Holes: C. lusitanae, Fusarium, Tricosporon, ScedosporiumC. lusitanae, Fusarium, Tricosporon, Scedosporium

Candida

Aspergillus

Cryptococcus

Coccidioides

Blastom

yces

Histoplasm

a

Fusarium

Tricosporon

Scedosporidium

Zygom

ycetes

albicans

glabrata

krusei

tropicalis

parapsilosis

lusitanae

+++

++

+++

+++

+++

-- ++

+++

+++

++

+++

+ + + +

Polyenes—Amphotericin BPolyenes—Amphotericin B

ResistanceResistance– Susceptibility testing methods have not Susceptibility testing methods have not

been standardizedbeen standardized– Development of resistance in a Development of resistance in a

previously susceptible species is previously susceptible species is uncommonuncommon

– Mechanisms of ResistanceMechanisms of Resistance Reductions in ergosterol biosynthesisReductions in ergosterol biosynthesis Synthesis of alternative sterols that lessen Synthesis of alternative sterols that lessen

the ability of amphotericin B to interact with the ability of amphotericin B to interact with the fungal membranethe fungal membrane

Polyenes—Amphotericin BPolyenes—Amphotericin B

FormulationsFormulations Amphotericin B deoxycholate Amphotericin B deoxycholate

– FungizoneFungizone Amphotericin B colloidal dispersionAmphotericin B colloidal dispersion

– Amphotec, AmphocilAmphotec, Amphocil Amphotericin B lipid complex Amphotericin B lipid complex

– AbelectAbelect Liposomal amphotericin B Liposomal amphotericin B

– AmbisomeAmbisome

Isolated from Isolated from Streptococcus nodosus Streptococcus nodosus in 1955in 1955 Amphotericin B is “amphoteric”Amphotericin B is “amphoteric”

– Soluble in both basic and acidic environmentsSoluble in both basic and acidic environments– Insoluble in waterInsoluble in water

Amphotericin B deoxycholateAmphotericin B deoxycholate Distributes quickly out of blood and into liver and other Distributes quickly out of blood and into liver and other

organs and slowly re-enters circulationorgans and slowly re-enters circulation– Long terminal-phase half-life (15 days)Long terminal-phase half-life (15 days)

Penetrates poorly into CNS, saliva, bronchial secretions, Penetrates poorly into CNS, saliva, bronchial secretions, pancreas, muscle, and bonepancreas, muscle, and bone

DisadvantagesDisadvantages– Glomerular Nephrotoxicity—Dose-dependent decrease in GFR Glomerular Nephrotoxicity—Dose-dependent decrease in GFR

because of vasoconstrictive effect on afferent renal arteriolesbecause of vasoconstrictive effect on afferent renal arterioles Permanent loss of renal function is related to the total cumulative Permanent loss of renal function is related to the total cumulative

dosedose– Tubular Nephrotoxicity—K, Mg+, and bicarbonate wastingTubular Nephrotoxicity—K, Mg+, and bicarbonate wasting– Decreased erythropoietin productionDecreased erythropoietin production– Acute Reactions—chills, fevers, tachypneaAcute Reactions—chills, fevers, tachypnea

SupportSupport– FluidsFluids– Potassium replacementPotassium replacement– Avoid concurrent nephrotoxic agentsAvoid concurrent nephrotoxic agents– Premed with acetaminophen, diphenhydramine or Premed with acetaminophen, diphenhydramine or

hydrocortisonehydrocortisone– Meperidine for rigorsMeperidine for rigors

Dose: 0.3 to 1 mg/kg once dailyDose: 0.3 to 1 mg/kg once daily

Amphotericin B Colloidal DispersionAmphotericin B Colloidal Dispersion(Amphotec)(Amphotec)

Cholesterol sulfate in equimolar Cholesterol sulfate in equimolar amounts to amphotericin Bamounts to amphotericin B

Similar kinetics to amphotericin B Similar kinetics to amphotericin B deoxycholatedeoxycholate

Acute infusion related reactions similar Acute infusion related reactions similar to amphotericin B deoxycholateto amphotericin B deoxycholate

Reduced rates of nephrotoxicity Reduced rates of nephrotoxicity compared to amphotericin B compared to amphotericin B deoxycholatedeoxycholate

DoseDose– 3 to 4 mg/kg once daily3 to 4 mg/kg once daily

Amphotericin B Lipid ComplexAmphotericin B Lipid Complex(Abelcet)(Abelcet)

Equimolar concentrations of amphotericin and Equimolar concentrations of amphotericin and lipidlipid

Distributed into tissues more rapidly than Distributed into tissues more rapidly than amphotericin B deoxycholateamphotericin B deoxycholate– Lower Cmax and smaller AUC than amphotericin Lower Cmax and smaller AUC than amphotericin

deoxycholatedeoxycholate– Highest levels achieved in spleen, liver, and lungsHighest levels achieved in spleen, liver, and lungs– Delivers drug into the lung more rapidly than AmbisomeDelivers drug into the lung more rapidly than Ambisome– Lowest levels in lymph nodes, kidneys, heart, and brainLowest levels in lymph nodes, kidneys, heart, and brain

Reduced frequency and severity of infusion Reduced frequency and severity of infusion related reactionsrelated reactions

Reduced rate of nephrotoxicityReduced rate of nephrotoxicity DoseDose

– 5 mg/kg once daily5 mg/kg once daily

Liposomal Amphotericin B Liposomal Amphotericin B (AmBisome)(AmBisome)

Liposomal productLiposomal product– One molecule of amphotericin B per 9 molecules of lipidOne molecule of amphotericin B per 9 molecules of lipid

DistributionDistribution– Higher Cmax and larger AUCHigher Cmax and larger AUC– Higher concentrations achieved in liver, lung, and spleenHigher concentrations achieved in liver, lung, and spleen– Lower concentrations in kidneys, brain, lymph nodes and Lower concentrations in kidneys, brain, lymph nodes and

heartheart– May achieve higher brain concentrations compared to other May achieve higher brain concentrations compared to other

amphotericin B formulationsamphotericin B formulations

Reduced frequency and severity of infusion Reduced frequency and severity of infusion related reactionsrelated reactions

Reduced rate of nephrotoxicityReduced rate of nephrotoxicity DoseDose

– 3 to 6 mg/kg once daily3 to 6 mg/kg once daily

FlucytosineFlucytosine MOAMOA

– Converted by cytosine Converted by cytosine deaminase into 5-fluorouracil deaminase into 5-fluorouracil which is then converted through which is then converted through a series of steps to 5-a series of steps to 5-fluorouridine triphosphate and fluorouridine triphosphate and incorporated into fungal RNA incorporated into fungal RNA leading to miscodingleading to miscoding

– Also converted by a series of Also converted by a series of steps to 5-fluorodeoxyuridine steps to 5-fluorodeoxyuridine monophosphate which is a monophosphate which is a noncompetitive inhibitor of noncompetitive inhibitor of thymidylate synthase, interfering thymidylate synthase, interfering with DNA synthesiswith DNA synthesis

Fluorinated pyrimidine

FlucytosineFlucytosine Spectrum of ActivitySpectrum of Activity

– Active againstActive against CandidaCandida species except species except C. kruseiC. krusei Cryptococcus neoformansCryptococcus neoformans Aspergillus Aspergillus speciesspecies

– Synergy with amphotericin B has been demonstrated Synergy with amphotericin B has been demonstrated The altered permeability of the fungal cell membrane produced The altered permeability of the fungal cell membrane produced

by amphotericin allows enhanced uptake of flucytosineby amphotericin allows enhanced uptake of flucytosine Mechanisms of ResistanceMechanisms of Resistance

– Loss of cytosine permease that permits flucytosine to cross Loss of cytosine permease that permits flucytosine to cross the fungal cell membranethe fungal cell membrane

– Loss of any of the enzymes required to produce the active Loss of any of the enzymes required to produce the active forms that interfere with DNA synthesisforms that interfere with DNA synthesis

Resistance occurs frequently and rapidly when flucytosine is Resistance occurs frequently and rapidly when flucytosine is given as monotherapygiven as monotherapy

Combination therapy is necessaryCombination therapy is necessary

FlucytosineFlucytosine Half-lifeHalf-life

– 2 to 5 hours in normal renal function2 to 5 hours in normal renal function– 85 hours in patients with anuria85 hours in patients with anuria

Distributes into tissues, CSF, and body fluidsDistributes into tissues, CSF, and body fluids ToxicitiesToxicities

– Bone marrow suppression (dose dependent)Bone marrow suppression (dose dependent)– Hepatotoxicity (dose dependent)Hepatotoxicity (dose dependent)– EnterocolitisEnterocolitis

Toxicities occur more commonly in patients with renal Toxicities occur more commonly in patients with renal impairmentimpairment

DoseDose– Administered orally (available in 250 and 500 mg capsules)Administered orally (available in 250 and 500 mg capsules)– 100 to 150 mg/kg/day in 4 divided doses100 to 150 mg/kg/day in 4 divided doses– Dose adjust for creatinine clearanceDose adjust for creatinine clearance

Flucytosine concentrations should be monitored Flucytosine concentrations should be monitored especially in patients with changing renal functionespecially in patients with changing renal function

Contraindicated in pregnancyContraindicated in pregnancy

TriazolesTriazoles MOA: Inhibits 14-MOA: Inhibits 14-α-α-

sterol demethylase, sterol demethylase, which is a microsomal which is a microsomal CYP450 enzyme. This CYP450 enzyme. This enzyme is responsible for conversion of lanosterol to ergosterol, the major sterol of most fungal cell membranes

Triazoles—Spectrum of ActivityTriazoles—Spectrum of ActivityFluconazole Itraconazole Voriconazole Posaconazole

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

C. glabrata + + ++ ++

C. krusei -- + +++ ++

C. tropicalis +++ ++ +++ +++

C. parapsilosis +++ ++ +++ +++

C. lusitanae ++ ++ +++ +++

Aspergillus -- ++ +++ +++

Cryptococcus +++ +++ +++ +++

Coccidioides +++ +++ +++ +++

Blastomyces ++ +++ ++ +++

Histoplasma + +++ ++ +++

Fusarium -- -- ++ ++

Scedosporium -- +/- + +/-

Zygomycetes - - - ++

Triazoles—ADMETriazoles—ADMEFluconazole Itraconazole Voriconazole Posaconazole

Absorption IV and POGood bioavailability

POCapsule ≠ SuspensionCapsules best absorbed with food.Suspension best absorbed on empty stomach.

IV and PO90% oralbioavailability

PO--Absorption enhanced withhigh fat meal

Distribution Wide. Good CNSpenetration

Low urinary levelsPoor CNSpenetration

Wide. Good CNSpenetration

Widelydistributed intotissues

Metabolism Hepatic/Renal Hepatic CYP 2C9, 2C19,3A4Saturablemetabolism

Not a substrate ofor metabolized byP450, but it is anInhibitor of 3A4

Elimination 80% excreted unchanged in the urine

Excreted in feces Minimal renalexcretion

Minimal renalexcretion of parentcompound66% excreted in feces

Triazoles—FluconazoleTriazoles—Fluconazole DoseDose

– 100 to 400 mg daily100 to 400 mg daily– Renal impairment:Renal impairment:

CrCl >50 ml/min, give full doseCrCl >50 ml/min, give full dose CrCl<50 ml/min, give 50% of doseCrCl<50 ml/min, give 50% of dose Dialysis: replace full dose after each sessionDialysis: replace full dose after each session

Drug InteractionsDrug Interactions– Minor inhibitor of CYP 3A4Minor inhibitor of CYP 3A4– Moderate inhibitor of CYP 2C9Moderate inhibitor of CYP 2C9

Warfarin, phenytoin, cyclosporine, tacrolimus, Warfarin, phenytoin, cyclosporine, tacrolimus, rifampin/rifabutin, sulfonylureasrifampin/rifabutin, sulfonylureas

Adverse Drug ReactionsAdverse Drug Reactions– Well toleratedWell tolerated– NauseaNausea– Elevated LFTsElevated LFTs

UNC Hospital Formulary

Triazoles—ItraconazoleTriazoles—Itraconazole DoseDose

– 200 to 400 mg/day (capsules)200 to 400 mg/day (capsules) doses exceeding 200 mg/day are given in 2 divided doses 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 Loading dose: 200 mg 3 times daily can be given for the first 3

daysdays– Oral solution is 60% more bioavailable than the capsulesOral solution is 60% more bioavailable than the capsules

Drug InteractionsDrug Interactions– Major substrate of CYP 3A4Major substrate of CYP 3A4– Strong inhibitor of CYP 3A4Strong inhibitor of CYP 3A4– Many Drug InteractionsMany Drug Interactions

Adverse Drug ReactionsAdverse Drug Reactions– Contraindicated in patients with CHF due to negative inotropic Contraindicated in patients with CHF due to negative inotropic

effectseffects– QT prolongation, torsades de pointes, ventricular tachycardia, QT prolongation, torsades de pointes, ventricular tachycardia,

cardiac arrest in the setting of drug interactionscardiac arrest in the setting of drug interactions– HepatotoxicityHepatotoxicity– RashRash– HypokalemiaHypokalemia– Nausea and vomitingNausea and vomiting

Triazoles—VoriconazoleTriazoles—Voriconazole DoseDose

– IVIV 6 mg/kg IV for 2 doses, then 3 to 4 mg/kg IV every 12 6 mg/kg IV for 2 doses, then 3 to 4 mg/kg IV every 12

hourshours

– PO PO > 40 kg—200-300 mg PO every 12 hours> 40 kg—200-300 mg PO every 12 hours < 40 kg—100-150 mg PO every 12 hours< 40 kg—100-150 mg PO every 12 hours

CirrhosisCirrhosis: : – IVIV

6 mg /kg IV for 2 doses, then 2 mg/kg IV every 12 6 mg /kg IV for 2 doses, then 2 mg/kg IV every 12 hourshours

– POPO > 40 kg—100 mg PO every 12 hours> 40 kg—100 mg PO every 12 hours < 40 kg— 50 mg PO every 12 hours< 40 kg— 50 mg PO every 12 hours

Renal impairmentRenal impairment: : if CrCl<50 ml/min, use oral formulation to avoid if CrCl<50 ml/min, use oral formulation to avoid

accumulation of cyclodextrin solubilizeraccumulation of cyclodextrin solubilizer

Triazoles—VoriconazoleTriazoles—Voriconazole

Common Adverse EffectsCommon Adverse Effects– Peripheral edemaPeripheral edema– Rash (6%)Rash (6%)– N/V/DN/V/D– HepatotoxicityHepatotoxicity– HeadacheHeadache– Visual disturbance (30%)Visual disturbance (30%)– FeverFever

Serious Adverse EventsSerious Adverse Events– Stevens-Johnson SyndromeStevens-Johnson Syndrome– Liver failureLiver failure– AnaphylaxisAnaphylaxis– Renal failureRenal failure– QTc prolongationQTc prolongation

Drug InteractionsDrug InteractionsMajor substrate of CYP 2CD and Major substrate of CYP 2CD and

2C192C19Minor substrate of CYP 3A4Minor substrate of CYP 3A4

Weak inhibitor of CYP 2C9 and Weak inhibitor of CYP 2C9 and 2C192C19

Moderate inhibitor of CYP 3A4Moderate inhibitor of CYP 3A4

Dose AdjustmentsDose AdjustmentsEfavirenzEfavirenzPhenytoinPhenytoin

CyclosporineCyclosporineWarfarinWarfarin

TacrolimusTacrolimus

Triazoles—PosaconazoleTriazoles—Posaconazole Dosing (only available PO)Dosing (only available PO)

– Prophylaxis of invasiveProphylaxis of invasive Aspergillus Aspergillus and and CandidaCandida species species 200 mg 3 times/day200 mg 3 times/day

– Treatment of oropharyngeal candidiasisTreatment of oropharyngeal candidiasis 100 mg twice daily for 1 day, then 100 mg once daily for 13 100 mg twice daily for 1 day, then 100 mg once daily for 13

daysdays– Treatment or refractory oropharyngeal candidiasisTreatment or refractory oropharyngeal candidiasis

400 mg twice daily400 mg twice daily– Treatment of refractory invasive fungal infections Treatment of refractory invasive fungal infections

(unlabeled use)(unlabeled use) 800 mg/day in divided doses800 mg/day in divided doses

Drug InteractionsDrug Interactions– Moderate inhibitor of CYP3A4Moderate inhibitor of CYP3A4

Adverse ReactionsAdverse Reactions– HepatotoxicityHepatotoxicity– QTc prolongationQTc prolongation– GI: DiarrheaGI: Diarrhea

EchinocandinsEchinocandinsMOAMOA

Irreversibly inhibits B-1,3 –D glucan synthase, Irreversibly inhibits B-1,3 –D glucan synthase, the enzyme complex that forms glucan the enzyme complex that forms glucan polymers in the fungal cell wall. Glucan polymers in the fungal cell wall. Glucan

polymers are responsible for providing rigidity polymers are responsible for providing rigidity to the cell wall. Disruption of B-1,3-D glucan to the cell wall. Disruption of B-1,3-D glucan synthesis leads to reduced cell wall integrity, synthesis leads to reduced cell wall integrity,

cell rupture, and cell death.cell rupture, and cell death.

Echinocandins—Spectrum of Echinocandins—Spectrum of ActivityActivity

Gallagher JC, et al. Expert Rev Anti-Infect Ther 2004;2:253-268

Candida

Aspergillus

Cryptococcus

Coccidioides

Blastom

yces

Histoplasm

a

Fusarium

Scedosporidium

Zygom

ycetes

albicans

glabrata

krusei

tropicalis

parapsilosis

lusitanae

guilliermondii

+++

+++

+++

+++

+ +++

+ +++

-- ++

++

-- - - -

EchinocandinsEchinocandins  Caspofungin Micafungin Anidulafungin

Absorption Not orally absorbed. IV only

Distribution Extensive into the tissues, minimal CNS penetration

Metabolism spontaneous degradation, hydrolysis and N-acetylation

Chemical degradated Not hepatically

metabolized

Elimination Limited urinary excretion. Not dialyzable

Half-life 9-23 hours 11-21 hours 26.5 hours

Dose 70 mg IV on day1, then 50 mg IVdaily thereafter

100 mg IVonce daily

200 mg IV on day 1,then 100 mg IVdaily thereafter

Dose Adjustment

Child-Pugh 7-970 mg IV on day 1, then 35 mg IV daily

thereafterCYP inducers70 mg IV daily

None None

Echinocandin—Drug Echinocandin—Drug InteractionsInteractions CaspofunginCaspofungin

– Not an inducer or inhibitor of CYP enzymesNot an inducer or inhibitor of CYP enzymes– CYP inducers (i.e. phenytoin, rifampin, carbamazepine)CYP inducers (i.e. phenytoin, rifampin, carbamazepine)

Reduced caspofungin levelsReduced caspofungin levels– Increase caspofungin doseIncrease caspofungin dose

– CyclosporineCyclosporine Increases AUC of caspofunginIncreases AUC of caspofungin HepatotoxicityHepatotoxicity

– Avoid or monitor LFTsAvoid or monitor LFTs– TacrolimusTacrolimus

Reduced tacrolimus levels by 20%Reduced tacrolimus levels by 20%– Monitor levels of tacrolimusMonitor levels of tacrolimus

MicafunginMicafungin– Minor substrate and weak inhibitor of CYP3A4 Minor substrate and weak inhibitor of CYP3A4 – NifedipineNifedipine

Increased AUC (18%) and Cmax (42%) of nifedipineIncreased AUC (18%) and Cmax (42%) of nifedipine– SirolimusSirolimus

Increased concentration of sirolimusIncreased concentration of sirolimus AnidulafunginAnidulafungin

– No clinically significant interactionsNo clinically significant interactionsCappelletty et al. Pharmacotherapy 2007;27:369-88

Echinocandins—Adverse Echinocandins—Adverse EffectsEffects

Generally well toleratedGenerally well tolerated Phlebitis, GI side effects, HypokalemiaPhlebitis, GI side effects, Hypokalemia Abnormal liver function testsAbnormal liver function tests CaspofunginCaspofungin

– Tends to have higher frequency of liver Tends to have higher frequency of liver related laboratory abnormalitiesrelated laboratory abnormalities

– Higher frequency of infusion related pain Higher frequency of infusion related pain and phlebitisand phlebitis

ReferencesReferences Gallagher JC, et al. Expert Rev Anti-Infect Ther 2004;2:253-268 UNC Hospital FormularyUNC Hospital Formulary Patel R. Antifungal Agents. Part I. Amphotericin B Preparations and Patel R. Antifungal Agents. Part I. Amphotericin B Preparations and

Flucytosine. Mayo Clin Proc 1998;73:1205-1225Flucytosine. Mayo Clin Proc 1998;73:1205-1225 Terrel CL. Antifungal Agents. Part II. The Azoles. Mayo Clin Proc Terrel CL. Antifungal Agents. Part II. The Azoles. Mayo Clin Proc

1999;74:78-100.1999;74:78-100. Mehta J. Do variations in molecular structure affect the clinical Mehta J. Do variations in molecular structure affect the clinical

efficacy and safety of lipid based amphotericin B preparations? Leuk efficacy and safety of lipid based amphotericin B preparations? Leuk Res. 1997;21:183-188.Res. 1997;21:183-188.

Groll AH et al. Penetration of lipid formulations of amphotericin B into Groll AH et al. Penetration of lipid formulations of amphotericin B into cerebral fluid and brain tissue. 37cerebral fluid and brain tissue. 37thth ICAAC, 1997. Abstract A90. ICAAC, 1997. Abstract A90.

Gallagher JC et al. Recent advances in antifungal pharmacotherapy Gallagher JC et al. Recent advances in antifungal pharmacotherapy for invasive fungal infections. Expert Rev. Anti-infect. Ther 2004; 2: for invasive fungal infections. Expert Rev. Anti-infect. Ther 2004; 2: 253-268.253-268.

Groll AH et al. Antifungal Agents: In vitro susceptibility testing, Groll AH et al. Antifungal Agents: In vitro susceptibility testing, pharmacodynamics, and prospects for combination therapy. Eur J pharmacodynamics, and prospects for combination therapy. Eur J Clin Microbiol Infect Dis 2004;23:256-270.Clin Microbiol Infect Dis 2004;23:256-270.

Capelletty D et al. The echinocandins. Pharmacotherapy Capelletty D et al. The echinocandins. Pharmacotherapy 2007;27:369-388.2007;27:369-388.

Spanakis EK et al. New agents for the treatment of fungal infections: Spanakis EK et al. New agents for the treatment of fungal infections: clinical efficacy and gaps in coverage. Clin Infect Dis 2006;43:1060-8.clinical efficacy and gaps in coverage. Clin Infect Dis 2006;43:1060-8.

Rex JH, Stevens DA. Systemic Antifungal Agents. In: Mandell GL, Rex JH, Stevens DA. Systemic Antifungal Agents. In: Mandell GL, Bennet JE, Dolin R, eds. Bennet JE, Dolin R, eds. Mandell, Douglas, and Bennett’s: Principles Mandell, Douglas, and Bennett’s: Principles and Practice of Infectious Diseases.and Practice of Infectious Diseases. Vol 1. 6 Vol 1. 6thth ed. New York, NY: ed. New York, NY: McGraw-Hill;2005:502.McGraw-Hill;2005:502.