Antifungal Drugs

Diseases due to fungal pathogensSuperficial Mycoses ----- Infections limited to the outermost layers

of the skin and hair--.- Malassezia furfur, Exophiala werneckii, Piedraia hortai, Trichosporum beigelii

Cutaneous mycoses Dermatophytes (Tinea)----- skin, hair and nails

Sub cutaneous mycoses------- Dermis, subcutaneous tissues, muscle and fascia

Sporotrichosis Sporothrix schenckii

Chromoblastomycosis Fonsecaeapedrosoi Fonsecaeacom pacta Wangielladermatitidis

Mycetoma Pseudallescheria boydii, Madurella grisea, Madurella mycetomatis

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Systemic Mycoses Originate primarily in the lung and may spread to many organ systems

• Coccidiodes immitis Coccidiomycosis.• Histoplasma capsulatum intracellular mycosis of the RES.• Blastomyces dermatitidis lungs and may disseminate to skin and other sites.

Opportunistic Mycoses Patients with immune deficiencies who would otherwise not be infected

Candida albicans mouth (thrush), female genitalia (vulvovaginitis), skin and nails.

Disseminated: thrombophlebitis, endocarditis, and involvement in

other organs such as the lungs and kidneys.fourth leading cause of bloodstream infections.

• Cryptococcus neoformansmeningitis in AIDS patients.

• Aspergillus lung, brain, sinuses, or other organs in immunosuppressed patients.

• Mucormycosis sinuses, eyes, blood, brain.

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Antifungal Drugs: Outline

• Polyenes (amphotericin B, nystatin)• Flucytosine• Azoles (imidazoles and triazoles)• Allylamines• Echinocandins• Griseofulvin• Other drugs

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Fungal cell Mannoproteins

-(1,6)-glucan-(1,3)-glucan

Chitin

Phospholipid bilayerof cell membrane

Cell membrane and cell wall

Ergosterol-(1,3)-glucan synthase

Squalene

ErgosterolSynthesisPathway

DNA/RNA Synthesis

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PolyenesAmphotericin B

Chemical properties - amphoteric aqueous insolubility at neutral pH

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Mechanism of action

• Amphotericin B is a heptaene macrolide; its amphoteric behavior results from a carboxyl group on the main ring and a primary amino group on mycosamine that confer aqueous solubility at pH extremes.

• It binds to fungal membrane sterols (ergosterol) and alters permeability selectively to K+ and Mg2+.

• Resistance may develop from altered sterols or decreased sterols. It is cidal.

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+ a polyene

ergosterol

ergosterol withpore

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Pharmacokinetics• I.V., Topical and I.T. (T½ - 24 hours)

• Amphotericin B in plasma is >90% bound to proteins.

• Mostly metabolized in liver.

• Some is excreted by kidney

• Concentrations of amphotericin B in fluids from inflamed pleura, peritoneum, synovium, and aqueous humor are approximately two-thirds of plasma trough conc.

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Spectrum

• Most systemic fungi

• Against the protozoa, Leishmania braziliensis and Naegleria fowleri, but has no antibacterial activity

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Preparations• Dispersed in deoxycholate

• Lipid formulation (Shape of particles) (type of lipid formulation)

• Abelcet (Ribbons) (Has particles of dimyristoyl phospholipid) --------ABLC

• Amphotec (Disks) (Has cholesteryl sulfate)-------ABCD

• AmBisome (Spheres) (Has complex liposomal mixture—made of lecithin and other biodegradable phospholipids)-- SUV

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Lipid formulation 20 to 50 times more expensive than Amb-B deoxycholate

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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 Nephrotoxicity—Dose-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 Nephrotoxicity—K, Mg+, and bicarbonate wasting– Decreased erythropoietin production(can cause hypochromic normocytic

anemia)– Acute Reactions—chills, fevers, tachypnea

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• 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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Afferent arteriole

Efferent arteriole

Proximaltubule Distal

tubule

Glomerulus

Direct damage of distal tubular membranes leading to wasting of Na+, K+, and Mg++

Constriction of the afferent arterioles leading to decreasedglomerular filtration

Tubular-glomerular feedback:Further constriction of arterioles

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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 other amphotericin

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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Ergosterol binds

Lipid Formulation Cholesterol>

Affinity for amphotericin B

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Nystatin

• Similar to amphotericin B.

• Used topically and for GI use.

• Used against candida and dermatophytes (epidermophyton, trichophyton, microsporum).

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N

HN

F

NH2

O

Flucytosine

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Mechanism of action

• Taken up into the fungal cell by means of

permease • Converted to 5-fluorouracil (5-fu) by cytosine

deaminase• 5-fu eventually inhibits thymidylate synthetase• Synthesized to 5-FUTP• Incorporated into RNA.

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5-FC

5-FC

5-FU

Cytosine permeaseCytosine permease

Cytosine deaminaseCytosine deaminase

PhosphorylationPhosphorylation

Inhibition of thymidylate synthaseInhibition of thymidylate synthase

FdUMP

Conversion todeoxynucleosidesConversion todeoxynucleosides

dUMP

dTMP

Inhibition of DNA synthesisInhibition of DNA synthesis

Inhibition of Protein SynthesisInhibition of Protein Synthesis

FdUMP

FUTP

Substitution for uracilSubstitution for uracil

5-FC, 5-fluorocytosine; 5-FU, 5-fluorouracil; FdUMP, 5-fluorodeoxyuridine;FUMP, 5-fluorouridine monophosphate; FUDP, 5-fluorouridine diphosphate;FUTP, 5-fluorouridine triphosphate; dUMP, deoxyuridine monophosphate;dTMP, deoxythymidine monophosphate

5-FC

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Uses

• Systemic fungi, mainly candida, and cryptococcus.

• Fungistatic.

• Used with amphotericin B (cryptococcal meningitis) and with itraconazole (chromoblastomycosis).

• It is given orally at 100 mg/kg/day, in divided doses at 6-hour intervals

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Pharmacokinetics

• T ½ ~ 3-6 hours

• Penetrates into CNS

• Excreted in urine-80% unchanged

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Untoward effects

• Nausea, vomiting, colitis

• Bone marrow suppression

• Thrombocytopenia

• Alopecia

• Decreased liver function

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Azoles

• Imidazoles

• Triazoles

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Azoles• MOA: Inhibits 14-α-sterol demethylase, which is a microsomal

CYP450 enzyme. This enzyme is responsible for conversion of lanosterol to ergosterol, the major sterol of most fungal cell membranes

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Acetyl CoA

Squalene

Lanosterol

(ergosterol)

Allylaminedrugs

Azoles

Squalene-2,3 oxide

Squalene monooxygenase

14--demethylase

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Resistance & Spectrum of imidazoles

• May develop by altered demethylase or

• By enhanced removal from the fungal cell.

• Acts on systemic fungi, dermatophytes - fungistatic

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Ketoconazole

• Blastomycosis, coccidioidomycosis, ringworm, candidiasis; given orally.

• Acid environment is needed to dissolve drug, does not enter the CNS well.

• Metabolized in liver and has a half-life of 3-6 hrs.

• Mostly fecal excretion after metabolism.

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Adverse effects and drug-drug interactions

• Nausea, vomiting• Allergic rash• Hormone imbalance---Gynaecomastia,loss of hair,and libido and

oligozoospermia,abnormal menses.• Fluid retention• Hepatitis

• Teratogenic—CI in pregnant women

• Inhibits drug metabolism

• Absorption reduced by H2 antihistamines and omeprazole and antacids

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Triazoles (a type of azole)Itraconazole: uses

• Blastomycosis

• Histoplasmosis

• Sporotrichosis

• Aspergillosis

• Candidiasis—Oropharangeal and esophageal(solution used as reserved drug in HIV)

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Itraconazole• Variable absorption when given orally, metabolized (one

active metabolite-Hydroxyitraconazole ) approx. h/l 30 hr.

• Fecal and renal excretion after extensive metabolism

• Capsules better absorbed in fed state and solution in empty stomach.

• For deep mycoses, a loading dose of 200 mg of itraconazole is administered three times daily for 3 days.

• Thereafter, two 100-mg capsules are given twice daily with food. 34

Itraconazole: untoward effects• Nausea, vomiting• Liver dysfunction• Hypokalemia

• Hypertriglyceridemia—2 to 10%

• CHF—in pts with left ventricular disfunction.• Drug-drug interactions, similiar to ketoconazole but to lesser

degree • Doses of 300 mg twice daily have led to adrenal insufficiency,

lower limb edema, hypertension, and rhabdomyolysis; therefore, doses above 400 mg/day are not recommended for long-term use

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Fluconazole• Almost completely absorbed from the GI tract irrespective of

food or gastric acidity

• Enters CNS .

• t½ - 25 – 30 hours, excreted unchanged

• Adverse effects- headache, N&V, rash, alopecia, rarely liver failure

• Least effect of all azoles on liver enzymes

• Uses – cryptococcal meningitis, candidiasis, coccidioidomycosis

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• 200 mg on the first day and then 100 mg daily for at least 2 weeks, is effective in oropharyngeal candidiasis

• A single dose of 150 mg is effective in uncomplicated vaginal candidiasis

• Cryptococcosis---400 mg/day, is used for the initial 8 weeks

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Voriconazole• Given iv and orally

• Absorption complete irrespective of food.

• Primary therapy of invasive aspergillosis.

• Esophageal and as salvage therapy in patients with P. boydii and Fusarium infections.

• Similar to itraconazole in spectrum

• Little interaction at CYP450,A/E –hepatotoxicity,QTc interval prolongation,visual changes

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Posaconazole

• For Invasive candidiasis, aspergillosis and Zygomycetes infections

• Only orally available

• Inhibits CYP3A4

• Adverse effects include: GI effects, dizziness, cardiac arrhythmias, abnormal liver function

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Effect of azoles on C. albicans

Before exposure After exposure

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Topical Azoles• Clotrimazole

• Miconazole

• Econazole

• Oxiconazole

• Sertaconazole

• Terconazole

• Sulconazole

• Tioconazole

• Butoconazole

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Terbinafine

• Inhibits squalene 2, 3- epoxidase. Squalene is cidal to sensitive organisms.

• Used orally for dermatophytes

• Metabolized in liver then excreted in urine

• Adverse effects include hepatitis and rashes. Both are rare.

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Terbinafine

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Naftifine, Amorolfine, and Butenafine

• Other allylamines• For topical use

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Caspofungin

• A large cyclic compound – an echinocandin

• Inhibits 1,3--D-glucan synthase, which is required for glucan polymerization in the wall of certain fungi

• Used for aspergillosis and candidiasis

• Used for empiric antifungal therapy

• Not absorbed orally. After intravenous injection, eliminated with t1/2 of ~10 hours.

• This drug that may be synergistic with amphotericin B and the azoles.

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Echinocandins act at the apical tips of Aspergillus hyphae

20024630011246

Micafungin,Anidulafungin

• Echinocandins for candidiasis

• Adverse effects are similar to caspofungin

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Echinocandins   CaspofunginCaspofungin MicafunginMicafungin AnidulafunginAnidulafungin

AbsorptiAbsorptionon

Not orally absorbed. IV onlyNot orally absorbed. IV only

DistributDistributionion

Extensive into the tissues, minimal CNS Extensive into the tissues, minimal CNS penetrationpenetration

MetaboliMetabolismsm

spontaneous degradation, spontaneous degradation, hydrolysis and N-acetylation hydrolysis and N-acetylation

Chemical Chemical degradated degradated

Not hepatically Not hepatically metabolizedmetabolized

EliminatiEliminationon

Limited urinary excretion. Not dialyzableLimited urinary excretion. Not dialyzable

Half-lifeHalf-life 9-23 hours9-23 hours 11-21 11-21 hourshours

26.5 hours26.5 hours

DoseDose 70 mg IV on day70 mg IV on day1, then 50 mg IV1, then 50 mg IVdaily thereafterdaily thereafter

100 mg IV100 mg IVonce dailyonce daily

200 mg IV on day 200 mg IV on day 1,1,

then 100 mg IVthen 100 mg IVdaily thereafterdaily thereafter

Dose Dose AdjustmAdjustm

entent

Child-Pugh 7-9Child-Pugh 7-970 mg IV on day 70 mg IV on day 1, then 35 mg IV 1, then 35 mg IV daily thereafterdaily thereafterCYP inducersCYP inducers70 mg IV daily70 mg IV daily

NoneNone NoneNone

Echinocandins—Adverse Effects

• Generally well tolerated• Phlebitis, GI side effects, Hypokalemia• Abnormal liver function tests• Caspofungin

– Tends to have higher frequency of liver related laboratory abnormalities

– Higher frequency of infusion related pain and phlebitis

GRISEOFULVIN

Mechanism of action

• Binds to microtubules comprising the spindles and inhibits mitosis.

• Incorporates into keratin and protects newly formed skin.

• Fungistatic.

• Spectrum -- Dermatophytes only

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Pharmacokinetics• Used orally, not topically

• Microsize and ultramicrosize preparations are used.

• Griseofulvin is detectable in the stratum corneum within 4–8 hours of oral administration.

• Sweat and transepidermal fluid loss play important roles in drug transfer to the stratum corneum

• Metabolized, then renal excretion

• T½ ~ 24 hours

• Several weeks of therapy are needed. 52

• Daily dose of griseofulvin is 5–15 mg/kg for children and 0.5–1 g for adults in DD at 6-hour intervals

• Requires 1 month for scalp and hair ringworm, 6–9 months for fingernails, and at least a year for toenails.

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Untoward effects • Nausea, headache(~15% of patients) • More serious ---Hepatoxicity & Renal toxicity, hematologic effects

(e.g., leukopenia, neutropenia, punctate basophilia, and monocytosis). Hypersensitivity;Blood study--- weekly required

• Estrogen-like effects have been observed in children.

• Induces hepatic CYPs

• Photosensitivity;Can precipitate acute intermittent porphyria

• Possibly teratogenic

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Topical agents• Cutaneous use are effective for tinea versicolor, and

cutaneous candidiasis. They are applied twice daily for 3–6 weeks.

• Vaginal creams, suppositories, and tablets for vaginal candidiasis ---used once daily for 1–7 days, preferably at bedtime to facilitate retention.

• None is useful in trichomoniasis. • Three vaginal formulations—clotrimazole tablets,

miconazole suppositories, and terconazole cream—come in both low- and high-dose preparations.

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Clotrimazole • 10-mg oral troche of used only in oropharyngeal

candidiasis for 14 days. • Absorption is <0.5% after application to intact skin;• From the vagina, 3–10%(2% vaginal cream or

vaginal tablets of 100mg-for 7days, 200mg--3days, or 500mg-single ).

• Fungicidal concentrations remain in the vagina for up to 3 days after drug application.

• Cure rate 80%-100%.56

Econazole

• Readily penetrates the stratum corneum and achieves effective concentrations down to the mid-dermis.

• Less than 1% of an applied dose is absorbed into the blood.

• Approximately 3% of recipients have local erythema, burning, stinging, or itching

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Miconazole

• Close chemical congener of econazole.• In the treatment of tinea pedis, tinea cruris, and

tinea versicolor, the cure rate is >90%. • In the treatment of vulvovaginal candidiasis, the

cure rate after 1 month is ~80–95%.

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Terconazole and Butoconazole

• Terconazole--- 80-mg vaginal suppository is inserted at bedtime for 3 days,

• 0.4% vaginal cream is used for 7 days and the 0.8% cream for 3 days

• Butoconazole nitrate --2% vaginal cream. • Because of the slower response during

pregnancy, a 6-day course is recommended (during the second and third trimester).

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• Oxiconazole nitrate is available as a cream and lotion;

• Sulconazole as a solution and cream, and• Sertaconazole as a 2% cream.

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Ciclopirox Olamine

• May block amino acid transport - penetrates well

• Available as a 0.77% cream and lotion for the treatment of cutaneous candidiasis and for tinea corporis, cruris, pedis, and versicolor.

• Cure rates in the dermatomycoses and candidal infections range from 81–94%.

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• Haloprogin - Useful for dermatophytes,T.versicolor and candida, may cause burning.

• Tolnaftate - useful for dermatophytes but not candida - inhibits synthesis of macromolecules.

• Undecylenic Acid - Dermatophytes. Also approved for use in the treatment of diaper rash,and other minor dermatological conditions. Cure rate ---50%.Zinc undecylenate is marketed in combination with other ingredients. The zinc provides an astringent action

• KI - taken orally for cutaneous sporotrichosis - may cause a rash and irritation of salivary and lacrimal glands

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Summary of TreatmentsPathogen Primary Secondary

Aspergillus fumigatus

Voriconazole

Posaconazole

Itraconazole, Caspofungin

Amphotericin B

Blastomyces dermatidis

Itraconazole or Amphotericin B

Fluconazole

Candida albicans Fluconazole Amphotericin B Caspofungin Posaconazole Anidulafungin

Voriconazole, Itraconazole, Ketoconazole (topical – many)

Coccidioides immitis

Itraconazole, Fluconazole or Amphotericin B 63

Summary of Treatments

Pathogen Primary Secondary

Cryptococcus neoformans

Amphotericin B ± Flucytosine followed by Fluconazole

Itraconazole or Amphotericin B

Histoplasma capsulatum

Itraconazole or Amphotericin B

Fluconazole

Mucomycosis Amphotericin B Posaconazole

Sporothrix schenckii

Amphotericin B Itraconazole

Saturated solution of potassium iodide Updated from MedicalLetter, 2005 64

QUESTIONS

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