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ANTIFUNGAL AGENTS. subhash k. mohan. UHN – TML & Mount Sinai Hospital. What are they? Empirical Use Antifungal Susceptibility Testing Interpretation. antifungal agents. antifungal agents. What are they?. Griseofulvin Polyenes Azoles 5-FC Terbinafine Echinocandins. antifungal agents.

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antifungal agents
ANTIFUNGAL AGENTS

subhash k. mohan

UHN – TML & Mount Sinai Hospital

what are they empirical use antifungal susceptibility testing interpretation
What are they? Empirical UseAntifungal Susceptibility Testing Interpretation

antifungal agents

Subhash K. Mohan

antifungal agents3
antifungal agents

What are they?

Griseofulvin

Polyenes

Azoles

5-FC

Terbinafine

Echinocandins

Subhash K. Mohan

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antifungal agents

Mode of action

Amphotericin B binds to plasma membrane creating pores

Azoles inhibits cytochrome P450 enzymes in the fungal cell

5FC converts to 5FU, incorporated into RNA, abnormal proteins

Griseofulvin binds microtubule proteins, inhibit cell wall synthesis

Terbinafine is an ergosterol inhibitor useful for systemic mycosis

Echinocandins target their action on fungal cell wall

Subhash K. Mohan

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antifungal agents

Griseofulvin

Source Penicillium griseofulvum

Produced in 1939

Not used until 1958

Spectrum

Dermatophytes

Gentles first used orally in guinea pigs prior to its use in humans

Anti-inflammatory properties

Inhibits keratolytic action

Subhash K. Mohan

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antifungal agents

Polyenes

VERY

TOXIC

Polyenes are produced from Streptomyces

Cyclic molecules

Nystatin

Amphotericin B

Natamycin

Mepartricin

Broad spectrum

Subhash K. Mohan

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antifungal agents

Amphotericin B

Yellow powder, water insoluble

Bile salt allows solubility (weak association)

Floats free in the aqueous medium, causes toxic effects

Broad spectrum, binds to sterol in the cell membrane

Fungicidal activity @ 3 h with 1 µg/ml

Azole-amphotericin B is never synergistic

Amphotericin B and 5FC gives synergy

Candida lusitaniae is usually resistant to Amphotericin B

Subhash K. Mohan

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antifungal agents

Amphotericin B

Toxicity

  • early intolerance reaction
  • thrombophlebitis
  • nephrotoxicity
  • hematotoxic effects

The liposomal preparation of Amphotericin B reduces the risk of nephrotoxicity

Subhash K. Mohan

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antifungal agents

Azole Derivatives

A chemical pentacyclic structure with 2 nitrogen atoms

Water insoluble except fluconazole

Preferentially inhibit cytochrome P450 enzymes

Fungistatic, Modify cytochrome P450 enzyme

First generation Imidazoles:

Clotrimazole & Miconazole

Clotrimazole requires high doses – poorly tolerated

Parenteral dosages no longer available forMiconazole

Subhash K. Mohan

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antifungal agents

Cytochrome P 450 (CYP 450)

CYP is a host of enzymes that use iron to oxidize things

CYP disposes harmful substances by making them water-soluble

CYP is something like a hydroxyl group

P450-mediated oxidation is referred to as "Phase I metabolism”

CYP in man is found in the liver, small intestine

CYP is vital to the formation of cholesterol & steroids

NADPH + H+ + O2 + RH ==> NADP+ + H2O + R-OH

Subhash K. Mohan

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antifungal agents

CYP 450 …..

Fungal plasma membranes have nonpolar sterol (ergosterol)

Amphotericin B binds to ergosterol permitting rapid leakage

Cytochrome P450 catalyzes synthesis of ergosterol

Azole antifungal agents interfere with cytochrome P450

Subhash K. Mohan

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Ketoconazole

Orally well absorbed imidazole of second generation

Ketoconazole is the only imidazole for systemic use

CSF penetration is very weak

Hepatotoxicity restricts its use

Also interacts with other molecules

Subhash K. Mohan

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antifungal agents

Third generation azoles

Triazole derivatives (contain three nitrogen atoms)

Fluconazole

Itraconazole

Voriconazole

Posaconazole

Revuconazole

Satisfactory tolerability, Suitable for systemic use

Subhash K. Mohan

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antifungal agents

Fluconazole & Itraconazole

Fluconazole has been extensively used for yeast infections

Useful for systemic infections

Readily and completely absorbed by gastrointestinal tract

Distributed equally in different organs and tissue

Candida krusei Intrinsically resistant to fluconazole

Itraconazole is used to treat aspergillus infections

Entirely metabolized in the liver

Eliminated in the feces and urine

Subhash K. Mohan

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antifungal agents

Voriconazole is a modified fluconazole

A broad spectrum antifungal agent

Rapid absorption after oral administration

Distributes in tissues and body fluids

Metabolized in the liver

Eliminated in the urine in unchanged form

Azoles carry some side effects

Hepatotoxicity, gastrointestinal and endocrine toxicity

Skin rash, pruritis and other hypersensitivity

Subhash K. Mohan

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Clinical Indication

Miconazole has poor tolerability given by intravenous

Ketoconazole used for endemic & superficial mycosis

Fluconazole useful for C. albicans and Cryptococcus neoformans

Voriconazole & Posaconazole have similar spectrum as other azole

Itraconazole is used to treat bronchopulmonary aspergillosis

Adverse effects: gastrointestinal, hypersensitivity & hepatotoxicity

Subhash K. Mohan

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Echinocandins

Caspofungin

Caspofungin is semisynthetic, synthesized from Glarea lozyensis

Whitish powder, water & methanol soluble, fungicidal

Fungicidal against, Aspergilli, Candida and P. carinii

No cross resistance amongst strains resistant to Ampho B or azoles

No activity against Cryptococcus neoformans, Fusarium & Rhizopus

Effective against Pneumocystis carinii

Micafungin and Anidulafungin – are under investigation

Subhash K. Mohan

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Terbinafine

Terbinafine belongs to allylamines, synthetic, highly lipophilic

Oral and topical (cream) formulations

Terbinafine inhibits ergosterol biosynthesis

Used to treat superficial mycosis

Also useful against systemic mycosis (yeast & other fungi)

Adverse reactions to terbinafine are in general transient and mild

Subhash K. Mohan

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Antifungal susceptibility testing

Based on NCCLS M27-A document

Macrodilution

Microdilution

Disk diffusion

Agar dilution

E test

Variables: inoculum, medium, PH, incubation & temperature, MIC

Subhash K. Mohan

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antifungal agents

Macrodilution read after 48h – more stable – useful for low volume

Major problem “trailing point”

Microdilution read after 24h (high values @ 48h)

Colorimetric method better for Azoles

Redox reaction of Alamar blue eliminates trailing point

Colorimetric MIC high for Itraconazole and low for Fluconazole

Spectrophotometer reading micro platesis useful after agitated

Blank disks soaked in antifungals applied on agar surface

Agar dilution faster – more data needed for evaluation

E-test based on diffusion of concentration gradient - investigational

Useful for isolates being resistant to Amphotericin B

Subhash K. Mohan

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Medium

RPMI 1640 buffered, pH 7.0

Inoculum

0.5 McFarland (1 x 103 to 5 x 103 CFU/ml)

Drug dilution

10x macrodilution, 2x microdilution

Range

Fluconazole 0.12 to 64 µg/ml, others 0.03 to 16 µg/ml

Macrodilution

0.9 ml inoculum & 0.1 ml of 10x drug

Microdilution

100 µl inoculum & 100 µl of 2x drug

Growth control

Macrodilution 0.9 ml inoculum & 0.1 ml drug free medium

Microdilution 100 µl inoculum & 100 µl drug free medium

Interpretation

Amphotericin B – lowest concentration prevents growth

5-FC & Azoles 80% inhibition macrodilution & 50% microdilution

Subhash K. Mohan

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Interpreting antifungal test results (MIC: mg/L)

Antifungal

Susceptible

Susceptible – dose dependent

Intermediate

Resistant

Fluconazole

= or < 8

16 - 32

= or > 64

Itraconazole

= or < 0.125

0.25 – 0.5

= or > 1

5-FC

= or < 4

8 - 16

= or > 32

Voriconazole*

= or < 1

2

= or > 4

* Tentative approval

Guidelines have not been established for Amp. B and Ketoconazole

Subhash K. Mohan

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Question

Does empiric use of antifungal agents trigger resistance?

Antifungals show resistance more than they did in the past

Some fungi become resistant after exposure to antifungals

Are we going to hit MRSA like situation in mycology?

Highly unlikely

Antifungals are not over prescribed as antibiotics

Subhash K. Mohan