Antifungal agents

Antifungal AgentsAntifungal Agents


Drugs used to treat infections caused by fungiDrugs used to treat infections caused by fungi

• Systemic and topicalSystemic and topical

FungiFungi

• Also known as mycosesAlso known as mycoses

• Very large and diverse group of Very large and diverse group of microorganismsmicroorganisms

• Broken down into yeasts and moldsBroken down into yeasts and molds

YeastsYeasts

• Single-cell fungiSingle-cell fungi

• Reproduce by buddingReproduce by budding

• Very useful organismsVery useful organisms

– BakingBaking

– Alcoholic beveragesAlcoholic beverages

MoldsMolds

• MulticellularMulticellular

• Characterized by long, branching filaments Characterized by long, branching filaments called hyphaecalled hyphae

Mycotic InfectionsMycotic Infections

Four General TypesFour General Types

• CutaneousCutaneous

• SubcutaneousSubcutaneous

• SuperficialSuperficial

• Systemic*Systemic*

*Can be life-threatening*Can be life-threatening

*Usually occur in immunocompromised host*Usually occur in immunocompromised host


Candida albicansCandida albicans

• Due to antibiotic therapy, antineoplastics, Due to antibiotic therapy, antineoplastics, or immunosuppressantsor immunosuppressants

• May result in overgrowth and systemic infectionsMay result in overgrowth and systemic infections


In the mouth:In the mouth:

• Oral candidiasis or thrushOral candidiasis or thrush

• Newborn infants and immunocompromised patientsNewborn infants and immunocompromised patients


Vaginal candidiasis:Vaginal candidiasis:

• ““Yeast infection”Yeast infection”

• Pregnancy, diabetes mellitus, oral contraceptivesPregnancy, diabetes mellitus, oral contraceptives


SystemicSystemic

• Examples: amphotericin B, fluconazole, Examples: amphotericin B, fluconazole, ketoconazole, itraconazoleketoconazole, itraconazole

TopicalTopical

• Examples: clotrimazole, miconazole, nystatinExamples: clotrimazole, miconazole, nystatin


Broken down into four major groups based Broken down into four major groups based on their chemical structureon their chemical structure

• Polyenes: amphotericin B and nystatinPolyenes: amphotericin B and nystatin

• FlucytosineFlucytosine

• Imidazoles: ketoconazole, miconazole, clotrimazole, Imidazoles: ketoconazole, miconazole, clotrimazole, fluconazolefluconazole

• GriseofulvinGriseofulvin

Antifungal Agents:Antifungal Agents:Mechanism of ActionMechanism of Action

Polyenes: amphotericin B and nystatinPolyenes: amphotericin B and nystatin

• Bind to sterols in cell membrane liningBind to sterols in cell membrane lining

• Allow K+ & Mg++ to leak out, altering fungal cell Allow K+ & Mg++ to leak out, altering fungal cell metabolismmetabolism

• Result: fungal cell deathResult: fungal cell death


flucytosineflucytosine

• Also known as 5-fluorocytosine (antimetabolite)Also known as 5-fluorocytosine (antimetabolite)

• Taken up by fungal cells and interferes with DNA Taken up by fungal cells and interferes with DNA synthesissynthesis



Imidazoles Imidazoles ketoconazole, miconazole, clotrimazole, fluconazoleketoconazole, miconazole, clotrimazole, fluconazole

• Inhibit an enzyme, resulting in cell membrane Inhibit an enzyme, resulting in cell membrane leakingleaking

• Lead to altered cell membraneLead to altered cell membrane



griseofulvingriseofulvin

• Disrupts cell divisionDisrupts cell division

• Result: inhibited fungal mitosis (reproduction)Result: inhibited fungal mitosis (reproduction)

Antifungal Agents: Side EffectsAntifungal Agents: Side Effects

amphotericin Bamphotericin B“Shake and Bake”“Shake and Bake”

feverfever chillschills headacheheadache anorexiaanorexia

malaisemalaise nauseanausea hypotensionhypotension tachycardiatachycardia

muscle and joint painmuscle and joint pain

lowered potassium and magnesium levelslowered potassium and magnesium levels

*renal toxicity*renal toxicity

*neurotoxicity: seizures and paresthesias*neurotoxicity: seizures and paresthesias

Antifungal Agents: Side EffectsAntifungal Agents: Side Effects

fluconazolefluconazole

• nausea, vomiting, diarrhea, abdominal pain,nausea, vomiting, diarrhea, abdominal pain,

• increased liver function studiesincreased liver function studies

flucytosineflucytosine

• nausea, vomiting, anorexianausea, vomiting, anorexia

griseofulvingriseofulvin

• rash, urticaria, headache, nausea, vomiting, anorexiarash, urticaria, headache, nausea, vomiting, anorexia

Antifungal Agents: Antifungal Agents: Nursing ImplicationsNursing Implications

• Before beginning therapy, assess for Before beginning therapy, assess for hypersensitivity, possible contraindications, hypersensitivity, possible contraindications, and conditions that require cautious use.and conditions that require cautious use.

• Obtain baseline VS, CBC, liver function Obtain baseline VS, CBC, liver function studies, and ECG.studies, and ECG.

• Assess for other medications used Assess for other medications used (prescribed and OTC) in order to avoid (prescribed and OTC) in order to avoid drug interactions.drug interactions.


• Follow manufacturer’s directions carefully Follow manufacturer’s directions carefully for reconstitution and administration.for reconstitution and administration.

• Monitor VS of patients receiving IV infusions Monitor VS of patients receiving IV infusions every 15 to 30 minutes.every 15 to 30 minutes.

• During IV infusions, monitor I & O and During IV infusions, monitor I & O and urinalysis findings to identify adverse urinalysis findings to identify adverse renal effects.renal effects.

Antifungal Agents: Antifungal Agents: Nursing ImplicationsNursing Implicationsamphotericin Bamphotericin B

• To reduce the severity of the infusion-related To reduce the severity of the infusion-related reactions, pretreatment with an antipyretic reactions, pretreatment with an antipyretic (acetaminophen), antihistamines, and antiemetics (acetaminophen), antihistamines, and antiemetics may be given.may be given.

• A test dose of 1 mg per 20 mL 5% dextrose inA test dose of 1 mg per 20 mL 5% dextrose inwater infused over 30 minutes should be given.water infused over 30 minutes should be given.

• Use IV infusion pumps and the most distal Use IV infusion pumps and the most distal veins possible.veins possible.


• Tissue extravasation of fluconazole at the IV Tissue extravasation of fluconazole at the IV site may lead to tissue necrosis—monitor IV site may lead to tissue necrosis—monitor IV site carefully.site carefully.

• Oral forms of griseofulvin should be given Oral forms of griseofulvin should be given with meals to decrease GI upset.with meals to decrease GI upset.

• Monitor carefully for side/adverse effects.Monitor carefully for side/adverse effects.


Monitor for therapeutic effects:Monitor for therapeutic effects:

• Easing of the symptoms of infectionEasing of the symptoms of infection

• Improved energy levelsImproved energy levels

• Normal vital signs, including temperatureNormal vital signs, including temperature

Antifungal DrugsAntifungal Drugs

• Polyene antibiotics: Amphotericin B, nystatinPolyene antibiotics: Amphotericin B, nystatin

• Antimetabolites: 5-Fluorocytosine Antimetabolites: 5-Fluorocytosine

• Azoles:Azoles:

Imidazoles: Ketoconazole, miconazole (topical) Imidazoles: Ketoconazole, miconazole (topical)

Trizoles: Itraconazole, FluconazoleTrizoles: Itraconazole, Fluconazole

• GriseofulvinGriseofulvin

• Topical antifungal agents: imidazoles, polyenes Topical antifungal agents: imidazoles, polyenes and others.and others.

www.freelivedoctor.com

Drug of Choice for most systemic fungal infections. Even those susceptible to others but where the disease rapidly progressive, in Immunocompromized or involves CNS.


Model for Amphotericin B induced Model for Amphotericin B induced Pore in Cell MembranePore in Cell Membrane

In fungi: ergosterol in membranes: higher affinity thanmammalian cholesterol for AmB


Adverse EffectsAdverse Effects

• Acute: Infusion-relatedAcute: Infusion-related

– Chills, fever, dyspnea, nausea, vomiting, bronchospasm, Chills, fever, dyspnea, nausea, vomiting, bronchospasm, hypotension, convulsionshypotension, convulsions

• ChronicChronic

– NephrotoxicityNephrotoxicity

azotemia, impaired concentration, impaired urinary azotemia, impaired concentration, impaired urinary acidification, K & Mg wasting with hypokalemia and acidification, K & Mg wasting with hypokalemia and hypomagnesemiahypomagnesemia

– Normochromic, normocytic anemia Normochromic, normocytic anemia

(↓ erythropoietin)(↓ erythropoietin)


QA

SNGFRRE

RA

PGC

ΔP

PT

Kf

Influence of Amphotericin B Infusion on Influence of Amphotericin B Infusion on Determinants of Single Nephron GFRDeterminants of Single Nephron GFR


Influence of Amphotericin BInfluence of Amphotericin Bon intracellular Caon intracellular Ca++++ levels levelsin glomerular mesangial cellsin glomerular mesangial cells

Theory

Pore

↑ Na entry

Depolarization

Voltage-dep. Ca channels

Contractionwww.freelivedoctor.com

Calcium channel blockers are protective against AmB- nephrotoxicityin-vivo in rats

Salt loading is protective against nephrotoxicity in vivo in animals


Salt loading orSupplementsProtectAgainst AmB-NephrotoxicityIn Humans


Alternative Formulations to Decrease ToxicityAlternative Formulations to Decrease Toxicity


Lipid formulations:20-50 times more expensive than AmB-deoxycholate


Renal Effects of AmB-DOC & Liposomal AmB


f-AmBL-AmB

f-AmB

L-AmB

AmB-DOC

Differential Effects of L-AmB on Mammalian Differential Effects of L-AmB on Mammalian and Fungal Cells, in Contrast to free AmBand Fungal Cells, in Contrast to free AmB

RBCFungal Cell



5-Fluorocytosine5-FluorocytosineA fluorinated pyrimidineA fluorinated pyrimidine

• Converted to 5 fluorouracil by a deaminase then Converted to 5 fluorouracil by a deaminase then to 5-fdUMP, which inhibits thymidylate synthase to 5-fdUMP, which inhibits thymidylate synthase and DNA synthesisand DNA synthesis

• Selective toxicity to fungal cells (no deaminase Selective toxicity to fungal cells (no deaminase in mammalian cells)in mammalian cells)

• Resistance is common. Do not use alone, but in Resistance is common. Do not use alone, but in combination with AmB cryptococcal meningitiscombination with AmB cryptococcal meningitis

• Bone marrow toxicity – pancytopenia -reversibleBone marrow toxicity – pancytopenia -reversible


The AzolesThe AzolesImidazoles and TriazolesImidazoles and Triazoles

• Triazoles newer with fewer side effectsTriazoles newer with fewer side effects

• Impair synthesis of ergosterol; inhibit sterol 14 α-Impair synthesis of ergosterol; inhibit sterol 14 α-demethylase (of cyt. P450). Acumulation of demethylase (of cyt. P450). Acumulation of precursors which inhibit growth.precursors which inhibit growth.

• Mammalian cells can incorporate already formed Mammalian cells can incorporate already formed cholesterol; fungi have to synthesizecholesterol; fungi have to synthesize

• Adverse effects due to inhibition of mammalian Adverse effects due to inhibition of mammalian steroid synthesissteroid synthesis

• Drug interactions due to inbibition of cyt. P450 Drug interactions due to inbibition of cyt. P450 enzymes.enzymes.


KetoconazoleKetoconazole(older, more toxic, replaced by itraconazole, but less costly)(older, more toxic, replaced by itraconazole, but less costly)

• Absorption variable (better in acidic medium)Absorption variable (better in acidic medium)

• Poor concentration in CSFPoor concentration in CSF

• Metabolized by Cyt. P450 enzymesMetabolized by Cyt. P450 enzymes

• Adverse effects:Adverse effects:

- Nausea, anorexia, vomiting- Nausea, anorexia, vomiting

- Endocrine: menstrual abnormalities, gynecomastia, azoospermia, - Endocrine: menstrual abnormalities, gynecomastia, azoospermia, decreased libido and potencydecreased libido and potency

- Hypertension and fluid retention- Hypertension and fluid retention

- Hepatitis (rare-fatal)- Hepatitis (rare-fatal)

- Drug Interactions (inhibition of cyt. P450) - Drug Interactions (inhibition of cyt. P450)

• Therapeutic Use: coccidiomycosis, histoplasmosis if not severely Therapeutic Use: coccidiomycosis, histoplasmosis if not severely ill or immunocompromized. Oral, esophageal, mucocutaneous ill or immunocompromized. Oral, esophageal, mucocutaneous candidiasiscandidiasis


TriazolesTriazoles

ItraconazoleItraconazole

• Varied absorption. Varied absorption. Metabolized by cyt P450Metabolized by cyt P450

• Has less endocrine effects Has less endocrine effects but occur at high dosesbut occur at high doses

• Less hepatitisLess hepatitis

• Histoplasmosis and Histoplasmosis and blastomycosisblastomycosis

• Many drug interactions (due Many drug interactions (due to inhibition of cyt P4503A4)to inhibition of cyt P4503A4)

FluconazoleFluconazole

• Completely absorbed and Completely absorbed and better toleratedbetter tolerated

• Renal excretionRenal excretion

• Less endocrine effects Less endocrine effects

• Penetrates well into CSFPenetrates well into CSF

• Cryptococcal, coccidial Cryptococcal, coccidial meningitis. Candidiasis.meningitis. Candidiasis.

• Drug InteractionsDrug Interactions


Other Antifungal AgentsOther Antifungal Agents

GriseofulvinGriseofulvin

• Binds to microtubules/ Binds to microtubules/ disrupts mitosisdisrupts mitosis

• Deposits in keratin layersDeposits in keratin layers

• Dermatophytes actively Dermatophytes actively concentrate itconcentrate it

• Infections of skin, hair, nails; Infections of skin, hair, nails; Prolonged therapyProlonged therapy..

• Toxicity: headache, neuro & Toxicity: headache, neuro & hepatotoxicity, photo-sensitivity, hepatotoxicity, photo-sensitivity, carcinogenic.carcinogenic.

Topical AntifungalsTopical Antifungals

• For stratum corneum, For stratum corneum, mucosa, cornea by mucosa, cornea by dermatophytes & Candida.dermatophytes & Candida.

• Not for subcutaneous, nail or Not for subcutaneous, nail or hair infections.hair infections.

• Many azoles; Tolnaftate; Many azoles; Tolnaftate; nystatin (Candida only); nystatin (Candida only); naftifine; terbinafine; naftifine; terbinafine; Whitfield’s ointment Whitfield’s ointment (Benzoic+Salicylic Acid). (Benzoic+Salicylic Acid).


Documents

Antifungal agents