Antifungals Nagamani

7/28/2019 Antifungals Nagamani

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Antifungal Agents


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Antifungal Agents

Polyene antibiotic The polyene antibiotics bind with sterols in the fungal

cell membrane, principally ergosterol. This causes the

cell's contents to leak out and the cell dies. Animalcells contain cholesterol instead of ergosterol and sothey are much less susceptible.

Nystatin

Amphotericin B (may be administered liposomally) Natamycin

Rimocidin

Filipin Pimaricin


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Antifungal Agents

Imidazole and triazole The imidazole and triazole groups of antifungal drugs

inhibit the enzyme cytochrome P450 14-demethylase.This enzyme converts lanosterol to ergosterol, and isrequired in fungal cell membrane synthesis. These drugsalso block steroid synthesis in humans.

Imidazoles: Miconazole Bifonazole Ketoconazole Butoconazole

Clotrimazole Econazole Mebendazole Fenticonazole Isoconazole Oxiconazole Sertaconazole Sulconazole

Thiabendazole Tiaconazole


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Antifungal Agents

The triazoles are newer, and areless toxic and more effective:

Fluconazole Itraconazole

Ravuconazole

Posaconazole

Voriconazole


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Antifungal Agents

Allylamines

Allylamines inhibit the enzyme squalene

epoxidase, another enzyme required forergosterol synthesis:

Terbinafine - marketed as Lamisil

Amorolfine

Naftifine

Butenafine


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Antifungal Agents

Echinocandin

Echinocandins inhibit the synthesis of glucan

in the cell wall, probably via the enzyme 1,3-glucan synthase:

Anidulafungin

Caspofungin

Micafungin


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Antifungal agents

Increase of human fungal infectionsmainly due to advances in surgery, cancertreatment, critical care, increase in the use

of broad spectrum antibiotics and HIV

Increased number of patients at risk

Antifungals available : systemic drugs, oraldrugs for mucocutaneous infections andtopical drugs


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Antifungal Agents

Polyene antibiotic The polyene antibiotics bind with sterols in the fungal

cell membrane, principally ergosterol. This causes the

cell's contents to leak out and the cell dies. Animalcells contain cholesterol instead of ergosterol and sothey are much less susceptible.

Nystatin

Amphotericin B (may be administered liposomally) Natamycin

Rimocidin

Filipin Pimaricin


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POLYENE ANTIFUNGALS

AMPHOTERICIN B

NYSTATIN

Fungicidal against both filamentous andyeastlike fungi, Histoplasma, Blastomyces,Coccidioides, Cryptococcus, Cnadida,

Aspergillus and Sporotrichum

In vitro activity against some protozoa


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POLYENE ANTIFUNGALS

Generally acts on sterols in thecytoplasmic membrane of fungi leading torapid leakage and fungal death


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AMPHOTERICIN B: CHEMISTRY

Produced by Streptomyces nodosus

Polyene macrolide

Water insoluble, prepared as a colloidalsuspension or in a lipid associated deliverysystem


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AMPHOTERICIN B: PHARMACOKINETICS

Poor GI absorption Oral administration is effective for fungal infections on

the lumen of the GI tract >90% protein bound

Serum t1/2 15 days Large Vd but CSF concentrations is only 2-3% of plasma

concentrations Poor CSF penetration, may require intrathecal

administration in cases of meningitis

Fugicidal and fungistatic


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AMPHOTERICIN B: LIPID FORMULATIONS

Therapy is limited by toxicity

Lipid binding of the drug causes lessbinding to mammalian membranespermitting the use of effective doses ofthe drug.

Lipid vehicle serves as a reservoir


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AMPHOTERICIN B: ADR

Infusion related toxicity: fever, chills,muscle spasms, vomiting, headache ,hypotension

Ameliorated by slow IV infusion ordecreasing the dose

Premedications with antihistamines

Start with a test dose


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AMPHOTERICIN B: ADR

Slower toxicity:

Azotemia is variable but can be serious enough tonecessitate dialysis

Renal toxicity commonly presents with RTA ( renaltubular acidosis with severe K and MG wasting)

Attenuated by preloading with saline

After intrathecal administration: seizures, chemical

arachoidits


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AMPHOTERICIN B: Antifungal activity

BROADEST SPECTRUM OF ACTIVITY

Candida albicans

Cryptococcus neoformans

Histoplasma capsulatum

Blastomyces dermatidis

Coccidioides imimtis

Aspergillus fumigatus

Candida lusitaniae and Pseudallescheria boydii areresistant


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AMPHOTERICIN B: Clinical Use

Drug of choice for nearly all life threathening mycoticinfections

Initial induction therapy for serious fungal infections andis concomitantly replaced by azoles

Fungal pneumonia, cryptococcal meningitis, sepsis,systemic fungal disease

Local application: Fungal keratitis, fungal arthritis,bladder irrigation in Candiduria


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PolyenesAmphotericin B

MOA: Binds toergosterol within thefungal cell membraneresulting in

depolarization of themembrane and theformation of pores. Thepores permit leakage of

intracellular contents.Exhibits concentrationdependent 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

CandidaAs

pergillus

Cryptococcus

Coccidioides

Blastomyces

Histoplasma

Fu

sarium

Tricosporon

Sc

edosporidiu

m

Zy

gomycetes

albicans

glabrata

krusei

tropicalis

parapsilosis

lusitanae

+++

++

+++

+++

+++

--

++

+++

+++

++

+++

+

+

+

+


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Resistance

Susceptibility testing methods have not beenstandardized

Development of resistance in a previouslysusceptible 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 fungalmembrane


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Formulations Amphotericin B deoxycholate

Fungizone

Amphotericin B colloidal dispersion

Amphotec, Amphocil Amphotericin B lipid complex

Abelect

Liposomal amphotericin B Ambisome

Isolated from Streptococcus nodosusin 1955Amphotericin B is amphoteric

Soluble in both basic and acidic environments Insoluble in water

h d h l


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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 Potassium 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 toamphotericin B

Similar kinetics to amphotericin Bdeoxycholate

Acute infusion related reactions similar toamphotericin 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 otheramphotericin 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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NYSTATIN

More soluble than Amphotericin B

Used primarily as a topical preparation

Active against most Candida species Not absorbed from skin or GI tract

No parenteral administration due to

toxicity


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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-fluorodeoxyuridinemonophosphate which is a

noncompetitive inhibitor of

thymidylate synthase, interfering

with DNA synthesis

Fluorinated pyrimidine


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Flucytosine Spectrum of Activity

Active against Candidaspecies except C. krusei

Cryptococcus neoformans

Aspergillusspecies

Synergy with amphotericin B has been demonstrated

The altered permeability of the fungal cell membrane produced byamphotericin 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 formsthat interfere with DNA synthesis

Resistance occurs frequently and rapidly when flucytosine is given asmonotherapy

Combination therapy is necessary


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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 especiallyin patients with changing renal function

Contraindicated in pregnancy


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Antifungal Agents

Imidazole and triazole The imidazole and triazole groups of antifungal drugs

inhibit the enzyme cytochrome P450 14-demethylase.This enzyme converts lanosterol to ergosterol, and is

required in fungal cell membrane synthesis. These drugsalso block steroid synthesis in humans.

Imidazoles: Miconazole Bifonazole Ketoconazole Butoconazole

Clotrimazole Econazole Mebendazole Fenticonazole Isoconazole Oxiconazole Sertaconazole Sulconazole

Thiabendazole Tiaconazole


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AZOLES

Synthetic compounds

Imidazoles: Ketoconazole, Miconazole,Clotrimazole

Triazoles: Itraconazole, Fluconazole,Vorioconazole


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AZOLES: Mechanism of Action

Reduction of ergosterol synthesis byionhibition of fungal cytochrome P450enzymes


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AZOLES: Clinical use

Candida species

Cryptococus neoformasns

B;astomyces

Coccidiomycosis Histoplasmosis

Dermatophytes

Aspergillus for Itraconazole and Voriconazole

Pseudallscheria boydii


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AZOLES: ADRs

Relatively non toxic

Minor GI upset

Abnormalities in liver enzymes


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Triazoles MOA: Inhibits 14--

sterol demethylase,which is a microsomalCYP450 enzyme. Thisenzyme is responsiblefor conversion of

lanosterol to ergosterol,the major sterol ofmost fungal cellmembranes

Triazoles Spectrum of Activity


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TriazolesSpectrum 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 ADME


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TriazolesADMEFluconazole Itraconazole Voriconazole Posaconazole

Absorption IV and POGood

bioavailability

POCapsule SuspensionCapsules bestabsorbed with food.

Suspension best

absorbed on emptystomach.

IV and PO

90% oral

bioavailability

PO--Absorption

enhanced with

high fat meal

Distribution Wide.Good CNSpenetration

Low urinary levelsPoor CNS

penetration

Wide.Good CNS

penetration

Widelydistributed into

tissues

Metabolism Hepatic/Renal Hepatic CYP 2C9, 2C19,3A4

Saturablemetabolism

Not a substrate of

or metabolized by

P450, but it is anInhibitor of 3A4

Elimination 80% excretedunchanged in the

urine

Excreted in feces Minimal renalexcretion

Minimal renal

excretion of parent

compound

66% excreted in

feces

Triazoles Fluconazole


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TriazolesFluconazole Dose

100 to 400 mg daily

Renal impairment: CrCl >50 ml/min, give full dose

CrCl


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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

Triazoles Voriconazole


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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 > 40 kg200-300 mg PO every 12 hours

< 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 > 40 kg100 mg PO every 12 hours

< 40 kg 50 mg PO every 12 hours

Renal impairment: if CrCl


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TriazolesVoriconazole

Common Adverse Effects Peripheral edema Rash (6%)

N/V/D Hepatotoxicity HeadacheVisual disturbance (30%) Fever

Serious Adverse Events

Stevens-Johnson Syndrome

Liver failure

Anaphylaxis

Renal failure

QTc prolongation

Drug Interactions

Major substrate of CYP 2CD and 2C19Minor substrate of CYP 3A4

Weak inhibitor of CYP 2C9 and 2C19Moderate inhibitor of CYP 3A4

Dose Adjustments

EfavirenzPhenytoin

CyclosporineWarfarin

Tacrolimus

Triazoles Posaconazole


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TriazolesPosaconazole Dosing (only available PO)

Prophylaxis of invasive Aspergillusand Candidaspecies 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

E hi di


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EchinocandinsMOA

Irreversibly inhibits B-1,3D glucan synthase, theenzyme complex that forms glucan polymers in thefungal 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.

h d f


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EchinocandinsSpectrum ofActivity

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

CandidaAspergillus

Cryptococcus

Coccidio

ides

Blastomyces

Histopla

sma

Fusarium

Scedosporidium

Zygomyc

etes

albic

ans

glabrata

krusei

tropi

calis

parapsilosis

lusitanae

guilliermondii

+++

+++

+++

+++

+ +++

+ +++

--

++ ++ -- - - -

Echinocandins


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EchinocandinsCaspofungin Micafungin Anidulafungin

Absorption Not orally absorbed. IV only

Distribution Extensive into the tissues, minimal CNS penetrationMetabolism 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 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

DoseAdjustment

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

then 35 mg IV daily

thereafter

CYP inducers

70 mg IV daily

None None

Echinocandin Drug Interactions


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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

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


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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 liverrelated laboratory abnormalities

Higher frequency of infusion related pain andphlebitis


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Itraconazole

Available in oral and IV formulations Drug absorption is increased by food or low gastric pH Reduced bioavailability when taken with Rifampicin,

Rifabutin, Rifapentine

Poor CSF penetration Drug of choice for HIstoplasma, Blastomyces and

Sporotrix infections Used extensively in the treatment of dematophytoses

and onychomycosis


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Fluconazole

Highly water soluble and high CSF penetration High oral bioavailability Better GI tolerance, fewer hepatic enzyme interactions:

widest therapeutic index

Azole of choice in the treatment and secondaryprophylaxis of Cryptococcal infections Equivalent to Amphotericin B in the treatment of

Candidemia Reduce fungal disease in bone marrow transplant and

AIDS patients


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Voriconazole

Good oral bioavailability

Low propensity for mammaliancytochrome P 450 inhibition

Causes Blurring of vision and altered colorperceptions

Excellent activity against Candida,effective in the treatment of invasive

Aspergillosis


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MICONAZOLE/ CLOTRIMAZOLE

Topically active

Fungicidal when administered topically

Poor CSF penetration

Used in ringworm infections andvulvovaginal candidiasis


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FLUCYTOSINE

Water soluble pyrimidine analog related to 5 FU

09% absorbed with peak serum concentrations 1-2hours after oral administration

Poor protein binding, penetrates well into all body fluidcompartments including CSF

Eliminated by glomerular filtration, levels rise rapidly inrenally impaired patients


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FLUCYTOSINE: ADRs

Toxicity related to the formation of 5 FU

Anemia, leukopenia, thrombocytopoenia

Narrow therapeutic window

Used in Cryptococcal infections


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Griseofulvin

Used in the systemic treatment ofdermatophytosis, Epidermophyton,Microsporum, Trichophyton,

Binds to keratin and is deposited in newlyforming skin


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Terbinafine

Used in the treatment of dermatophytosis,specifically onychiomycosis

Like Griseofulvin, it is Keratophyllic

Does not seem to affect cytochrome P450enzymes


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Echinocandins/ Capsofungin

Newest class of antifungals

Cyclic peptides linked to a long chain fattyacid

Acts at the level of the fungal wall byinhibiting the synthesis of beta 1-3 glucan,resulting in cell wall disruption

Used in Invasive Aspergillosis who havefailed to respond to Amphotericin B.


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Voriconazole

Voriconazole is available in oral andintravenous (IV) formulations

FDA approval in May 2002 Invasive aspergillosis

Scedosporium apiospermum (asexualform of Pseudallescheria boydii)

Fusarium spp. infections in patientsintolerant of, or refractory to, othertherapy


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Voriconazole

A synthetic derivative offluconazole Substitution of a triazole group with a

fluoropyrimidine moiety

increase potency and in vivo efficacyAddition of a methyl group to the propyl

backbone increasing the affinity of the drug for the target

enzyme (14--sterol demethylase)


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Voriconazole

Pharmacokinetics Maximum plasma concentrations

within 1 or 2 hours following dosing (similar for IV andoral route of administration)

The oral bioavailability: 96%

Extensive distribution in humans a steady-state volume of approximately 4.6 L/kg

Serum levels: 2 to 6 g/mL

Moderate binding to plasma proteins: 58%

Metabolized by the hepatic cytochrome P-450enzymes especially CYP2C19, CYP2C9, and CYP3A4

V i l


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Voriconazole

In vitro susceptibility testing Broad-spectrum in vitro activity

Candida spp

Cryptococcus

Scedosporium spp.

Trichosporon spp.

Aspergillus spp. including AmB-resistant clinical isolates

Blastomyces dermatitidis

Coccidioides immitis

Histoplasma capsulatum Dermatophytes

Epidermophyton floccosum

Microsporum spp

Trichophyton spp.


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Ravuconazole

Ravuconazole is similar to fluconazole with athiazole in the place of a second triazole

Ravuconazole is available only in an oralformulation

Phase II clinical trials

Long terminal half-life

100 hours

Well tolerated in

single doses of800 mg/d

400 mg/d for up to 14 days

Headache being the most reported adverse event


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Ravuconazole

In vitro susceptibility testing Broad spectrum of activity against

Aspergillus spp.

C neoformans Candida spp.

Trichosporon spp.

Dermatophytes

Trichophyton mentagrophytes Trichophyton rubrum

Microsporum gypseum

Microsporum canis

Epidermophyton floccossum


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Ravuconazole

In vivo studies

Safety and dose-dependent efficacy weredemonstrated in several animal models

Invasive and pulmonary aspergillosis

Candidiasis

Cryptococcosis

Histoplasmosis


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Ravuconazole

Oropharyngeal and esophageal candidiasisin immunocompromised humans 400 mg once daily

Response rate Ravuconazole: 86%

Fluconazole: 78%

Adverse events abdominal pain (8%)

diarrhea (6%)

pruritus (6%)

rash (6%)


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Ravuconazole

Dermatophyte infections

A phase I-II study of toenail onychomycosis

After 48 weeks, effective treatment rates

200 mg/d: 56%

effective and safe therapy for onychomycosis

100 mg/wk: 10%

400 mg/wk: 8%

Placebo: 15% Steady-state serum levels: 3000 ng/mL

successful clinical and mycologic response


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Posaconazole

An analogue ofitraconazole with a 1,3-dioxolone backbone

In phase III trials


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Posaconazole

Pharmacokinetics Well absorbed at oral concentrations of

200 mg every day

400 mg every day 200 mg four times a day

Half-life: 22 hours

Maximum concentrations: 3 hours after

dosing


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Posaconazole

In vitro susceptibility testing Broad spectrum of activity against

Aspergillus spp.

Candida spp. including strains resistant to fluconazole

C neoformans

Trichosporon spp.

Zygomycetes Dermatophytes

more effective against yeast and nondermatophytefungi


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Posaconazole

In vivo studies

In murine models

Invasive aspergillosis

Histoplasmosis

Coccidioidomycosis

Disseminated fusariosis

P boydii infections Mucor spp.


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Posaconazole

Animal models of superficial fungalinfections

Single oral dose of2.5 or 10 mg

more effective than fluconazole

Topical administration at 0.25 or 0.5%

more effective than

oral fluconazole

oral itraconazole topical miconazole

More effective in reducing fungal burden


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Posaconazole

Oropharyngeal candidiasis in amulticenter trial

a single dose of200 mg followed by

100 mg/d posaconazole vs fluconazole

similar clinical and mycologic responses

similar safety profiles


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Azole cross-resistance

Mechanisms of resistance to drugaction Modification of the drug itself

Modification in quantity or quality of thedrug target

Reduced access to the target

The resistance may result from acombination of these mechanisms


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Factors in resistance Overexpression of 14--demethylase

an azole-resistant strain of C glabrata

the mechanism of cross-resistance exhibitedwith itraconazole and fluconazole

Altered membrane sterol composition methylated sterols, such as methylfecosterol

replacing ergosterol an azole-resistant and polyene-resistant C

albicans mutant

A l i t


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These mechanisms may not be azole-specific Reduced susceptibility offluconazole-

resistant isolates of Candida spp. tovoriconazole and itraconazole an indication that azole cross-resistance is

developing

specific to isolates ofC tropicalis

cross-resistance can be species-specific

Potential cross-resistance ofitraconazolewith fluconazole 50 isolates of C neoformans


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Cross-resistance to itraconazole, miconazole,and voriconazole 13 isolates of S apiospermum

Posaconazole Not show cross-resistance with other four azoles

May have a mechanism of action or mechanism ofresistance that differs from the other azoles

A l i t


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Heterogeneity in susceptibility tothe azoles The similarity of MIC values for

voriconazole and ravuconazole similar modes of action

similar mechanisms of resistance

Posaconazole

not show elevations of MIC in conjunction withincreased MIC values of the azolesitraconazole, miconazole, and voriconazole

l


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Heterogeneity in susceptibility tothe azoles

differences in activity of azoles different mechanisms of resistance to the

azoles

explain the lack of cross-resistance between

some azoles despite apparent structuralsimilarities

Further studies into azole susceptibilityd

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Antifungals Nagamani