ANTIFUNGAL AGENTS

ANTIFUNGAL AGENTS

Antifungal agents• Increase of human fungal infections mainly

due to advances in surgery, cancer treatment, critical care, increase in the use of broad spectrum antibiotics and HIV

• Increased number of patients at risk• Antifungals available : systemic drugs, oral

drugs for mucocutaneous infections and topical drugs

Evolution of antifungal agents

POLYENE ANTIFUNGALSAMPHOTERICIN BNYSTATIN• Fungicidal against both filamentous and yeastlike

fungi, Histoplasma, Blastomyces, Coccidioides, Cryptococcus, Cnadida, Aspergillus and Sporotrichum

• In vitro activity against some protozoa• Generally acts on sterols in the cytoplasmic membrane

of fungi leading to rapid leakage and fungal death

AMPHOTERICIN B: CHEMISTRY• Produced by Streptomyces nodosus • Polyene macrolide • Water insoluble, prepared as a colloidal

suspension or in a lipid associated delivery system

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

AMPHOTERICIN B: MECHANISM OF ACTION• Binds to Ergosterol and alters cell permeability• Forms pores in the cell which allows leakage

of intracellular ions and macromolecules• Binds to human membrane sterols,

accounting for toxicity• Resistance if ergosterol binding is impaired

either by increasing ergosterol concentration or modifying the sterol of the target molecule

AMPHOTERICIN B: LIPID FORMULATIONS• Therapy is limited by toxicity• Lipid binding of the drug causes less binding to

mammalian membranes permitting the use of effective doses of the drug.

• Lipid vehicle serves as a reservoir

AMPHOTERICIN B: ADR• Infusion related toxicity: fever, chills, muscle spasms, vomiting,

headache , hypotension• Ameliorated by slow IV infusion or decreasing the dose• Premedications with antihistamines• Start with a test dose• Slower toxicity: • Azotemia is variable but can be serious enough to necessitate

dialysis• Renal toxicity commonly presents with RTA ( renal tubular acidosis

with severe K and MG wasting)• Attenuated by preloading with saline• After intrathecal administration: seizures, chemical arachoidits

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

are resistant

AMPHOTERICIN B: Clinical Use• Drug of choice for nearly all life threathening

mycotic infections• Initial induction therapy for serious fungal

infections and is concomitantly replaced by azoles

• Fungal pneumonia, cryptococcal meningitis, sepsis, systemic fungal disease

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

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

AZOLES

• Synthetic compounds– Imidazoles: Ketoconazole, Miconazole,

Clotrimazole– Triazoles: Itraconazole, Fluconazole, Vorioconazole

AZOLES: Mechanism of Action• Reduction of ergosterol synthesis by ionhibition

of fungal cytochrome P450 enzymes

AZOLES: Clinical use• Candida species• Cryptococus neoformasns• B;astomyces• Coccidiomycosis• Histoplasmosis• Dermatophytes• Aspergillus for Itraconazole and Voriconazole• Pseudallscheria boydii

AZOLES: ADRs• Relatively non toxic• Minor GI upset• Abnormalities in liver enzymes

Ketoconazole• Systemic use discontinued because of its great

propensity to inhibit mammalian cytochrome P450 enzymes

• Used in dermatologic infections

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

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 secondary

prophylaxis of Cryptococcal infections• Equivalent to Amphotericin B in the treatment of

Candidemia• Reduce fungal disease in bone marrow transplant and

AIDS patients

Voriconazole• Good oral bioavailability• Low propensity for mammalian cytochrome P

450 inhibition• Causes Blurring of vision and altered color

perceptions• Excellent activity against Candida, effective in

the treatment of invasive Aspergillosis

MICONAZOLE/ CLOTRIMAZOLE• Topically active• Fungicidal when administered topically• Poor CSF penetration• Used in ringworm infections and vulvovaginal

candidiasis

FLUCYTOSINE

• Water soluble pyrimidine analog related to 5 FU

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

• Poor protein binding, penetrates well into all body fluid compartments including CSF

• Eliminated by glomerular filtration, levels rise rapidly in renally impaired patients

FLUCYTOSINE: Mechanism of Action• Taken up by fungal cells via cytosine permease• Converted to 5FU and the to 5

fluorodeoxyuridine 5 F-dUMP and fluorouidine 3 PO4

• Inhiobits DNA and RNA synthesis• Resistance seen in monotherapy• Acts synergystically with Amphotericin B.

FLUCYTOSINE: ADRs• Toxicity related to the formation of 5 FU• Anemia, leukopenia, thrombocytopoenia• Narrow therapeutic window• Used in Cryptococcal infections

Griseofulvin

• Used in the systemic treatment of dermatophytosis, Epidermophyton, Microsporum, Trichophyton,

• Binds to keratin and is deposited in newly forming skin

Terbinafine

• Used in the treatment of dermatophytosis, specifically onychiomycosis

• Like Griseofulvin, it is Keratophyllic• Does not seem to affect cytochrome P450

enzymes

Echinocandins/ Capsofungin

• Newest class of antifungals • Cyclic peptides linked to a long chain fatty acid• Acts at the level of the fungal wall by

inhibiting the synthesis of beta 1-3 glucan, resulting in cell wall disruption

• Used in Invasive Aspergillosis who have failed to respond to Amphotericin B.

To determine the susceptibility of fungi to antifungal agents

• Concentration that inhibits the growth of fungi = Minimum inhibitory concentration (expressed as µg/ml) Several methods can be used to define the MIC MIC reading = depends on the method used(EUCAST, CLSI, E-test,…)

MICs defined via E-test

Growth of fungus

MIC= zone of inhibition

–MICs help, but hard to standardize –Correlations appear possible based on individual isolates.

Broad correlations based on multiple isolates are still lacking–Understanding this helps a lot when trying to correlate

outcome with MIC- Some patients get better despite MICs - Some patients just don’t get better despite MICs

–No rule when it correlates/not correlates

AZOLE RESISTANT ASPERGILLUS FUMIGATUS

Antifungal susceptibility testing

Macrodilution

Microdilution

Disk diffusion

E test

Agar dilution

Based on NCCLS M27-A document

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

Azole cross-resistance

• Mechanisms of resistance to drug action – Modification of the drug itself– Modification in quantity or quality of the drug

target– Reduced access to the target

• The resistance may result from a combination of these mechanisms

Factors in resistance – Modifications of the azoles have not yet been

documented as a factor– Differing binding affinities of azoles• Some species of Candida

– Efflux of fluconazole • development of fluconazole resistance in some Candida

species• achieved by increased expression of the multidrug

resistance transporter proteins (especially MDR1)

• Factors in resistance– Overexpression of 14-α-demethylase • an azole-resistant strain of C glabrata• the mechanism of cross-resistance exhibited with

itraconazole and fluconazole – Altered membrane sterol composition • methylated sterols, such as methylfecosterol replacing

ergosterol• an azole-resistant and polyene-resistant C albicans

mutant