anti fun gals

8/8/2019 Anti Fun Gals

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Antifungals

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Fungal pathogens

Superficial mycoses are the most

common infections. Oral candidiasis/candidosis with themajority of these infections are causedby Candida albicans.

Risk factors: corticosteroid therapy,broad-spectrum antibiotic, diabetesand immunosuppression.

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C. albicans, normal component of GIflora, compete with bacteria and arekept in check by the immune system.

Candida, dimorphous fungi, live in ayeast state,

replicate by budding (C).

U

nder appropriate conditions,Candida can chan e into an invasive

C D


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Systemic fungal infections

Fungal infections arecharacteristic ofHIV, cancer,and patients receiving broad-

spectrum antibiotics orimmunosuppressive agents.

Are a major cause of death.

The fungi involved in includeCandida, Histoplasma,

Aspergillus, and Cryptococcus

species.3


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Antifungal Pharmacotherapy:

All drugs known to

humans are poisons, onlythe amountordose

determine the effects.

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Paracelsus

14931541


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Main classes of antifungals

A.Azoles inhibit Erg11:block the production ofergosterol and causethe accumulation of a

toxic sterolintermediate, whichresults in cellmembrane stress.

B.Polyenes bind to

ergosterol, formingpores in cellmembranes.

C. 5-flucytosine inhibits DNA 5

Antifungal mechanisms


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SUMMARY ofAntifungalMechanisms:

The majority of

antifungalsinhibitbiosynthesis orstability ofergosterol,

a majorcomponent of

fungal cellmembrane.

Ergosterol servesthe same

functions in6

Antifungals affect

ergosterol by:1. Bind to ergosterol

and block its

function.

2. Block ergosterolsynthesis by

inhibiting enzymelanosterol

demethylase.

3. Block ergosterolsynthesis by

inhibiting proteinsqualene synthase.

HO

CH3 H H3C

CH3

H3C

H

H

HO

CH3 H3C

CH3

H3C

H

H

CH3

CH3

CH3

H

H

Cholesterol

Ergosterol


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Resistance to antifungal drugs

esistance: mutations in expression

of the target protein, lanosteroldemethylase

drug transport: Efflux pumps

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Azoles inhibit lanosterol 14-a demethylase (ERG11) (pinkcircle), blocking the formation of ergosterol.efflux transportproteins : encoded by either MDR or CDR


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Candidiasis pharmacotherapy

Oral candidiasis is treatedtopically with topicalnystatin

Azoles is an alternative

treatment, with oral fluconazoleas the next line of therapy.

In extreme cases, intravaneousamphotericin with flucytosinemay be considered.

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Q: Bacteria and fungi infect some of the same

areas of the body. How can you distinguish

bacterial and fungal infections?


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Drug Classes:

Polyenes: nystatin (topical),amphotericin (topical,systemic)

Imidazoles: clotrimazole,ketoconazole

Triazoles: fluconazole

Routes of Administration:


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Polyene: NystatinBinds to sterols(preferentially

ergosterol)

Disruption osmoticintegrity

of fungal membraneLeakage ofintracellularcomponents

Fungal death

Amphotericin B: conc-dependent fungicidal:Cmax/MIC

against Candida, Cryptococcusand A. fumigatus

PK/PD relationship in vivo :

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-clinical treatment with AMB is

limited by


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Polyenes

Nystatin (NY laboratory) acts by binding to the fungal

cell membrane sterol resultingin permeability changes and cell

lysis.a) Uses: similar to amphotericin Bexcept that it is used only fortopical treatment or oral candidosis

b) Administration:There is minimalabsorption orally, but can be used fororal candidiasis. It has an extremelybitter taste which limits its use.

c)Side effects: minimal when used 11

Not absorbed from skin, mucous membranes,or GI tract.


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Topical Antifungals for Thrush

For topical agents, successdepends on contact time

(minimum of2 minutes)

Treat 4-5 times per day

Treatment duration varies (7-14

d)2-3 days beyond last clinicalsymptoms


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Old Standard: Nystatin

Polyene antifungalw

ith broadspectrum

Concentration-dependent fungicidalactivity

Increased concentrations results inincreased rate and/or extent of

killing

Fungistatic at 0.5 2 x MIC

Fungicidal at >2 x MIC (C. kruseirequired 4x MIC)

Rate of kill de endent s onGunderson SM, et al. AntimicrobAgents Chemother 2000;44:2887-90.


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Azoles

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Description: Azoles are named for ringstructures within the drug.


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Azole drugs- inhibit ergosterol synthesis

Mechanism: by inhibitingfungalcytochrome p450 enzyme

activity, thus inhibitingconversion of methylsterol to

ergosterol, leading to cellulardisruption.

Side effects: Lanosterol

demethylase is a cytochromeP450 protein, related to humanlanosterol demethylase andother P450 proteins. As a result,

azole drugs inhibit human P450 15

lanosterol


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Azoles PK/PD

Conc-independent fungistatic agents Dosage escalation may be necessary when faced with

more resistant fungal species (e.g. Candida glabrata)

Goal of dosing is to maintain AUC:MIC >50effective therapy: AUC/MIC 25 (Candida spp.)

maintain concentrations 1-2 x MIC for the entire dosing

interval

Time-dependent and conc-dependent for

fungicidal activity against A. fumigatus

in


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Ketoconazole

The first oral azole introduced

into clinical use.

Less selective for fungal P450

Inhibition of human P450 interfereswith biosynthesis of adrenal andgonadal steroid hormones;

Alter the metabolism of other

drugs.

Best absorbed at a low gastricpH.

Miconazole, Econazole, Clotrimazole

Bioavailability is low by takingorally.

Used topically.17


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Clotrimazole

a)Uses: use for a number offungal infections, oropharyngeal

candidosis. It can also be used

cutaneously and intravaginally.b)Application: administered as a10 mg oral troche.

Its effects are purely topical.Clotrimazole = Lotrimin.

c)Side effects: Patients taking

oral troche experience gastric18

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