Antifungals_Mayer

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Antifungal AgentsAntifungal AgentsLindsay Mayer, PharmDLindsay Mayer, PharmD

October 26, 2007October 26, 2007


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PolyenesAmphotericin BPolyenesAmphotericin B

MOA: Binds toMOA: Binds toergosterol within theergosterol within the

fungal cellfungal cell

membrane resultingmembrane resulting

in depolarization ofin depolarization ofthe membrane andthe membrane and

the formation ofthe formation of

pores. The porespores. The pores

permit leakage ofpermit leakage of

intracellular contents.intracellular contents.

ExhibitsExhibits

concentrationconcentrationde endent killin .de endent killin .


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PolyenesAmphotericin BPolyenesAmphotericin 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,C. lusitanae, Fusarium, Tricosporon,

ScedosporiumScedosporium

+

Tr

icosporon

++++++

++

+++

+++

++

--

+++

+++

+++

++

+++

lusitanae

parapsilosis

tropicalis

krusei

glabrata

albicans

Zy

gomycetes

Scedosporidiu

m

Fu

sarium

Histoplasma

Blastomyces

Coccidioides

Cryptococcus

Aspergillus

Candida


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ResistanceResistance

Susceptibility testing methods have notSusceptibility testing methods have not

been standardizedbeen standardized

Development of resistance in aDevelopment of resistance in a

previously susceptible species ispreviously susceptible species is

uncommonuncommon

Mechanisms of ResistanceMechanisms of Resistance Reductions in ergosterol biosynthesisReductions in ergosterol biosynthesis

Synthesis of alternative sterols that lessenSynthesis of alternative sterols that lessen

the ability of amphotericin B to interact withthe ability of amphotericin B to interact with

the fungal membranethe fungal membrane


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FormulationsFormulations Amphotericin B deoxycholateAmphotericin B deoxycholate

FungizoneFungizone

Amphotericin B colloidal dispersionAmphotericin B colloidal dispersion

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

AbelectAbelect

Liposomal amphotericin BLiposomal amphotericin B AmbisomeAmbisome

Isolated from Streptococcus nodosus in 1955 Amphotericin B is amphoteric

Soluble in both basic and acidic environments Insoluble in water


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

other organs and slowly re-enters circulationother organs and slowly re-enters circulation

Long terminal-phase half-life (15 days)Long terminal-phase half-life (15 days) Penetrates poorly into CNS, saliva, bronchialPenetrates poorly into CNS, saliva, bronchial

secretions, pancreas, muscle, and bonesecretions, pancreas, muscle, and bone DisadvantagesDisadvantages

Glomerular NephrotoxicityDose-dependent decrease inGlomerular NephrotoxicityDose-dependent decrease in

GFR because of vasoconstrictive effect on afferent renalGFR because of vasoconstrictive effect on afferent renalarteriolesarterioles Permanent loss of renal function is related to the totalPermanent loss of renal function is related to the total

cumulative dosecumulative dose

Tubular NephrotoxicityK, Mg+, and bicarbonate wastingTubular NephrotoxicityK, Mg+, and bicarbonate wasting Decreased erythropoietin productionDecreased erythropoietin production

Acute Reactionschills, fevers, tachypneaAcute Reactionschills, fevers, tachypnea SupportSupport

FluidsFluids Potassium replacementPotassium replacement Avoid concurrent nephrotoxic agentsAvoid concurrent nephrotoxic agents

Premed with acetaminophen, diphenhydramine orPremed with acetaminophen, diphenhydramine orh drocortisonehydrocortisone


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Amphotericin B Colloidal DispersionAmphotericin B Colloidal Dispersion

(Amphotec)(Amphotec)

Cholesterol sulfate in equimolarCholesterol sulfate in equimolaramounts to amphotericin Bamounts to amphotericin B Similar kinetics to amphotericin BSimilar kinetics to amphotericin B

deoxycholatedeoxycholate Acute infusion related reactions similarAcute infusion related reactions similar

to amphotericin B deoxycholateto amphotericin B deoxycholate Reduced rates of nephrotoxicityReduced rates of nephrotoxicity

compared to amphotericin Bcompared to amphotericin Bdeoxycholatedeoxycholate

DoseDose

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


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Amphotericin B Lipid ComplexAmphotericin B Lipid Complex

(Abelcet)(Abelcet) Equimolar concentrations of amphotericinEquimolar concentrations of amphotericin

and lipidand lipid Distributed into tissues more rapidly thanDistributed into tissues more rapidly than

amphotericin B deoxycholateamphotericin B deoxycholate

Lower Cmax and smaller AUC than amphotericinLower Cmax and smaller AUC than amphotericindeoxycholatedeoxycholate Highest levels achieved in spleen, liver, and lungsHighest levels achieved in spleen, liver, and lungs Delivers drug into the lung more rapidly thanDelivers drug into the lung more rapidly than

AmbisomeAmbisome

Lowest levels in lymph nodes, kidneys, heart, andLowest levels in lymph nodes, kidneys, heart, andbrainbrain Reduced frequency and severity of infusionReduced frequency and severity of infusion

related reactionsrelated reactions Reduced rate of nephrotoxicityReduced rate of nephrotoxicity DoseDose


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Liposomal Amphotericin BLiposomal 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 andLower concentrations in kidneys, brain, lymph nodes andheartheart

May achieve higher brain concentrations compared to otherMay achieve higher brain concentrations compared to otheramphotericin B formulationsamphotericin B formulations

Reduced frequency and severity of infusionReduced frequency and severity of infusionrelated reactionsrelated reactions Reduced rate of nephrotoxicityReduced rate of nephrotoxicity DoseDose

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


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FlucytosineFlucytosine

MOAMOA Converted by cytosineConverted by cytosine

deaminase into 5-fluorouracildeaminase into 5-fluorouracil

which is then converted throughwhich is then converted through

a series of steps to 5-a series of steps to 5-fluorouridine triphosphate andfluorouridine triphosphate and

incorporated into fungal RNAincorporated into fungal RNA

leading to miscodingleading to miscoding

Also converted by a series ofAlso converted by a series of

steps to 5-fluorodeoxyuridinesteps to 5-fluorodeoxyuridine

monophosphate which is amonophosphate which is a

noncompetitive inhibitor ofnoncompetitive inhibitor of

thymidylate synthase, interferingthymidylate synthase, interfering

with DNA synthesiswith DNA synthesis

Fluorinated pyrimidine


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FlucytosineFlucytosine Spectrum of ActivitySpectrum of Activity

Active againstActive against CandidaCandida species exceptspecies except C. kruseiC. krusei

Cryptococcus neoformansCryptococcus neoformans

AspergillusAspergillus speciesspecies

Synergy with amphotericin B has been demonstratedSynergy with amphotericin B has been demonstrated

The altered permeability of the fungal cell membrane producedThe altered permeability of the fungal cell membrane producedby 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 crossLoss 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 activeLoss of any of the enzymes required to produce the activeforms that interfere with DNA synthesisforms that interfere with DNA synthesis

Resistance occurs frequently and rapidly when flucytosine isResistance occurs frequently and rapidly when flucytosine isgiven as monotherapygiven as monotherapy

Combination therapy is necessaryCombination therapy is necessary


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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 renalToxicities occur more commonly in patients with renalimpairmentimpairment

DoseDose Administered orally (available in 250 and 500 mgAdministered orally (available in 250 and 500 mgcapsules)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 monitoredFlucytosine concentrations should be monitoredes eciall in atients with chan in renal functiones eciall in atients with chan in renal function


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AzolesKetoconazoleAzolesKetoconazole UsesUses

Used in U.S. as an alternativeUsed in U.S. as an alternative

Non-albicans candidiasisNon-albicans candidiasis BlastomycosisBlastomycosis HistoplasmosisHistoplasmosis

Not for immunocompromised hosts due to high failure rateNot for immunocompromised hosts due to high failure rate

CoccidioidomycosisCoccidioidomycosis

Not for meningitis or for severely illNot for meningitis or for severely ill ParacoccidioidomycosisParacoccidioidomycosis

Inactive against non-albicans candida andInactive against non-albicans candida andAspergillusAspergillus

Needs acidic environment for absorptionNeeds acidic environment for absorption

Only available POOnly available PO Distributes into epidermis, synovial fluid, saliva, andDistributes into epidermis, synovial fluid, saliva, and

lungs. Poor distribution into CSF and eye.lungs. Poor distribution into CSF and eye. DoseDose

200 to 400 mg once daily200 to 400 mg once daily Decrease dose for severe liver failureDecrease dose for severe liver failure


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AzolesKetoconazoleAzolesKetoconazole Adverse EffectsAdverse Effects

GI distress (17-43%)GI distress (17-43%)

Rash (4-10%)Rash (4-10%) Increased transaminases (2-Increased transaminases (2-

10%)10%) Hepatitis (1 in 10,000)Hepatitis (1 in 10,000)

Can be fatal if drug is not DCdCan be fatal if drug is not DCd Usually occurs within first 4Usually occurs within first 4

months of treatmentmonths of treatment

Dose-dependent inhibition ofDose-dependent inhibition ofsynthesis of testosterone (5-synthesis of testosterone (5-21% of patients will have21% of patients will havesymptoms such as impotencesymptoms such as impotenceor gynecomastia)or gynecomastia)

Menstrual Irregularities (16%Menstrual Irregularities (16%

of women)of women) Alopecia (8%)Alopecia (8%) Dose-related decrease inDose-related decrease in

cortisol synthesiscortisol synthesis Hypermineralocorticoid stateHypermineralocorticoid state

Can cause HTN in patients onCan cause HTN in patients onlong-term high doselong-term high dose

ketoconazoleketoconazole Teratogenic in animalsTeratogenic in animals

Drug InteractionsDrug Interactions Antacids, H2 blockers, protonAntacids, H2 blockers, proton

pump inhibitors, sucralfatepump inhibitors, sucralfate Decreases absorption ofDecreases absorption of

ketoconazoleketoconazole

Rifampin decreasesRifampin decreasesketoconazole concentrationsketoconazole concentrationsby 33%by 33%

CYP inhibitionCYP inhibition

Cyclosporine levelsCyclosporine levelsincreasedincreased

WarfarinWarfarin PhenytoinPhenytoin MethylprednisoloneMethylprednisolone

IsoniazidIsoniazid TerfenadineTerfenadine AstemizoleAstemizole CisaprideCisapride


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

sterol demethylase,sterol demethylase,which is awhich is amicrosomal CYP450microsomal CYP450enzyme. Thisenzyme. Thisenzyme is

responsible forconversion oflanosterol toergosterol, themajor sterol of most

fungal cellmembranes


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TriazolesSpectrum of ActivityTriazolesSpectrum of Activity

++---Zygomycetes

+/-++/---Scedosporium

++++----Fusarium

+++++++++Histoplasma

++++++++++Blastomyces

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

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

++++++++--Aspergillus

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

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

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

++++++--C. krusei

++++++C. glabrata

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

PosaconazoleVoriconazoleItraconazoleFluconazole


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TriazolesADMETriazolesADME

Minimal renal

excretion of parent

compound

66% excreted in

feces

Minimal renal

excretion

Excreted in feces80% excreted

unchanged in the

urine

Elimination

Not a substrate of

or metabolized by

P450, but it is anInhibitor of 3A4

CYP 2C9, 2C19,

3A4

Saturablemetabolism

HepaticHepatic/RenalMetabolism

Widelydistributed into

tissues

Wide.Good CNS

penetration

Low urinary levelsPoor CNS

penetration

Wide.Good CNS

penetration

Distribution

PO--Absorption

enhanced with

high fat meal

IV and PO

90% oral

bioavailability

POCapsule Suspension

Capsules best

absorbed with food.

Suspension best

absorbed on empty

stomach.

IV and PO

Good

bioavailability

Absorption

PosaconazoleVoriconazoleItraconazoleFluconazole


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TriazolesFluconazoleTriazolesFluconazole 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


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TriazolesItraconazoleTriazolesItraconazole DoseDose

200 to 400 mg/day (capsules)200 to 400 mg/day (capsules)

doses exceeding 200 mg/day are given in 2 divided dosesdoses exceeding 200 mg/day are given in 2 divided doses Loading dose: 200 mg 3 times daily can be given for the first 3Loading 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 negativeContraindicated in patients with CHF due to negative

inotropic effectsinotropic effects

QT prolongation, torsades de pointes, ventricularQT prolongation, torsades de pointes, ventriculartachycardia, cardiac arrest in the setting of drugtachycardia, cardiac arrest in the setting of druginteractionsinteractions

HepatotoxicityHepatotoxicity

RashRash


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TriazolesVoriconazoleTriazolesVoriconazole DoseDose

IVIV 6 mg/kg IV for 2 doses, then 3 to 4 mg/kg IV every 126 mg/kg IV for 2 doses, then 3 to 4 mg/kg IV every 12

hourshours

POPO > 40 kg200-300 mg PO every 12 hours> 40 kg200-300 mg PO every 12 hours

< 40 kg100-150 mg PO every 12 hours< 40 kg100-150 mg PO every 12 hours

CirrhosisCirrhosis:: IVIV

6 mg /kg IV for 2 doses, then 2 mg/kg IV every 126 mg /kg IV for 2 doses, then 2 mg/kg IV every 12hourshours

POPO > 40 kg100 mg PO every 12 hours> 40 kg100 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


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TriazolesVoriconazoleTriazolesVoriconazole

Common AdverseCommon AdverseEffectsEffects Peripheral edemaPeripheral edema

Rash (6%)Rash (6%) N/V/DN/V/D HepatotoxicityHepatotoxicity HeadacheHeadache Visual disturbanceVisual disturbance

(30%)(30%)

Serious Adverse EventsSerious Adverse Events

Stevens-Johnson SyndroStevens-Johnson Syndrom

Liver failureLiver failure AnaphylaxisAnaphylaxis

Renal failureRenal failure

QTc prolongationQTc prolongation

Drug InteractionsDrug Interactions

Major substrate of CYP 2CD andMajor substrate of CYP 2CD and2C192C19

Minor substrate of CYP 3A4Minor substrate of CYP 3A4

Weak inhibitor of CYP 2C9 andWeak inhibitor of CYP 2C9 and

2C192C19

Moderate inhibitor of CYP 3A4Moderate inhibitor of CYP 3A4

Dose AdjustmentsDose Adjustments

EfavirenzEfavirenzPhenytoinPhenytoin

CyclosporineCyclosporine

WarfarinWarfarin

TacrolimusTacrolimus


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TriazolesPosaconazoleTriazolesPosaconazole Dosing (only available PO)Dosing (only available PO)

Prophylaxis of invasiveProphylaxis of invasive AspergillusAspergillus andand CandidaCandidaspeciesspecies 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 for100 mg twice daily for 1 day, then 100 mg once daily for

13 days13 days

Treatment or refractory oropharyngeal candidiasisTreatment or refractory oropharyngeal candidiasis 400 mg twice daily400 mg twice daily

Treatment of refractory invasive fungal infectionsTreatment 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


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EchinocandinsEchinocandinsMOAMOA

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

polymers are responsible for providing rigiditypolymers are responsible for providing rigidityto the cell wall. Disruption of B-1,3-D glucanto the cell wall. Disruption of B-1,3-D glucansynthesis leads to reduced cell wall integrity,synthesis leads to reduced cell wall integrity,

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


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EchinocandinsSpectrum ofEchinocandinsSpectrum of

ActivityActivity

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

-----

++

++

--

+++

++++

++++

+++

+++

+++

guilliermondii

lusitanae

para

psilosis

tropicalis

krusei

glabrata

albicans

Zygomycetes

Scedosporidium

Fusarium

Histopla

sma

Blastomyces

Coccidioides

Cryptococcus

Aspergillus

Candida

E hi diE hi di


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EchinocandinsEchinocandins

200 mg IV on day 1,

then 100 mg IV

daily thereafter

100 mg IV

once daily

70 mg IV on day

1, then 50 mg IV

daily thereafter

Dose

NoneNoneChild-Pugh 7-970 mg IV on day 1,

then 35 mg IV daily

thereafter

CYP inducers

70 mg IV daily

DoseAdjustment

26.5 hours11-21 hours9-23 hoursHalf-life

Limited urinary excretion. Not dialyzableElimination

Chemical degradated

Not hepatically

metabolized

spontaneous degradation,

hydrolysis and N-acetylation

Metabolism

Extensive into the tissues, minimal CNS penetrationDistribution

Not orally absorbed. IV onlyAbsorption

AnidulafunginMicafunginCaspofungin

u


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uInteractionsInteractions 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 CYP3A4Minor 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


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EchinocandinsAdverseEchinocandinsAdverse

EffectsEffects

Generally well toleratedGenerally well tolerated

Phlebitis, GI side effects,Phlebitis, GI side effects,

HypokalemiaHypokalemia

Abnormal liver function testsAbnormal liver function tests

CaspofunginCaspofungin

Tends to have higher frequency of liverTends to have higher frequency of liverrelated laboratory abnormalitiesrelated laboratory abnormalities

Higher frequency of infusion relatedHigher frequency of infusion related

pain and phlebitispain and phlebitis

R fR f


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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 andPatel 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 ProcTerrel 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 clinicalMehta J. Do variations in molecular structure affect the clinical

efficacy and safety of lipid based amphotericin B preparations? Leukefficacy 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 intoGroll 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 pharmacotherapyGallagher 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 Jpharmacodynamics, and prospects for combination therapy. Eur JClin Microbiol Infect Dis 2004;23:256-270.Clin Microbiol Infect Dis 2004;23:256-270.

Capelletty D et al. The echinocandins. PharmacotherapyCapelletty D et al. The echinocandins. Pharmacotherapy2007;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 edsBennet JE Dolin R eds Mandell Douglas and Bennetts: PrinciplesMandell Douglas and Bennetts: Principles

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