antifungal pharamcotherapy

7/28/2019 Antifungal Pharamcotherapy

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CHEMOTHERAPY

ANTIFUNGAL

DRUGS


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ANTI FUNGAL DRUGS

For superficial & deep fungal infections.

Dermatophytosesa common clinical problem

Additional importance in the current era of iatrogenic fungal

infections and

those due to immuno - compromised states (B/S Antibiotics,

C/steroids, cytotoxic drugs, implants, catheters, AIDS etc).


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CLASSIFICATION

I. SYSTEMIC DRUGS : Both oral & parenteral

Amphotericin-B, Flucytosine

Imidazoles : Ketoconazole

Triazoles : Itraconazole, Fluconazole, Voriconazole.

II. ORAL DRUGS FOR MUCOCUTANEOUS INF

Griseofulvin (Benzofuran), Terbinafine(Allylamine).

III. TOPICAL ANTIFUNGAL DRUGS :Nystatin, Hamycin, Clotrimazole, Econazole, Miconazole,

Tolnaftate, Cyclopiroxolamine, Undecylenic acid.


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AMPHOTERICIN - B A water insoluble polyene macrolide antibiotic

PKsVery poor oral abs, widely distributed, poor CSF entry, no

dosage adjustments needed in renal / hepatic dysfunction.

MOABinds to ergosterol in fungal memb formation of pores by

multiple molecules leakage of cell contents cell death.

ADRs Immediate : Fever, chills, vom, hypotension

(Can be minimized by slow infusion, NSAIDs, Antihist, steroids, test

dose of 1mg over 20 mins).

Long term: Nephrotoxic (Azotemia, acidosis,

hypokalemia etc) Anemia, Seizures, Encephalopathy


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AMPHOTERICINB (Contd) Antifungal spectrumCandida, Histoplasma, Cryptococcus,

Blastomyces, Coccidioides, Torulopsis, Aspergillus, Sporothrix,

Rhodotorula etc

Reserve drug for resistant/mucocut Leishmaniasis.

Dose : 50 mg dil in 500 ml 5% dextrose given as 0.3 mg/kg IVinfusion over 4-8 hrs. Can be sed to 0.7 mg/kg. Oral dose 50-100mg QID for int monilia.

Newer preparations :

(a) Amphoter icin-B L ipid Complex (ABLC)35% in ribbon likeparticles of dimyristoyl PLs

(b) Amphoter icin-B Colloidal Dispersion (ABCD)

50% drug + cholesteryl sulfate as disc shaped particles.


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AMPHOTERICINB (Contd)

(c) Liposomal Amphotericin-B [Small unilamellar Vesicles (SUV)]10%

AMB in lecithin liposomesbetter tolerated drug, better delivery.

Clinical uses : TopicalOral, vaginal & cutaneous candidiasis.

SystemicCryptococcosis, Coccidio, Blastomycosis,

Sporotrichosis, Aspergillosis etc.

Also, for resistant Kala Azar & mucocutaneous leishmaniasis.

Interaxns: Additive axn with 5-FC, axn by Rifampicin &

Minocycline. Nephrotoxicity by AGs, Vancomycin, Cyclosporine

etc.


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FLUCYTOSINE Pyrimidine anti-metabolite

Oral formulations available

Inhibits DNA & RNA synth, after getting conv to 5-FU5-f/deoxyuridylic acidinh of thymidylate synth. Selective. Mammalsconv into active metab

Synergistic action with Amphotericin-B

Well distributed, incl CSF. Eliminationprimarily renal

ADRsBM suppression, enterocolitis

UsesCryptococcal & Candida infections, Dose : 100-150 mg/kg/d in 4div doses.


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AZOLES

ImidazolesKetoconazole, Miconazole, Clotrimazole, Econazole

TriazolesItraconazole, Fluconazole.

MOAInh fungal lanosterol 14-demethylase reduced ergosterol

synthesis accumulation of 14methyl sterols membrane

abnormalities in fungus fungicidal / fungistatic. Selective, since

affinity for mammalian CYP 450 enzymes.


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KETOCONAZOLE

First oral azole, variable oral abs, low pH needed, metab in liver, excr

in urine & feces. t1/2

:2-6 hrs.

ADRs : Nausea, vom, appetite, paraesthesias, alopecia etc.

- Inhibits mammalian Cyt P450 too gonadal & adrenal steroid

synthesis gynaecomastia, libido & sperm counts etc, mildhepatotoxicity.

- C/Id in Preg & lactating ladies.

Alters drug metabolism (microsomal enz inhibitor), esp with

astemizole, terfenadine & cisapride T/de / pointes etc.


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Ketoconazole (Contd)

Interactions (Contd) - bld levels of warfarin, sulfonylureas,

diazepam, phenytoin, cyclosporin, nifedipine, indinavir.

- Drugs sing gastric pH will Ketoconazole abs

- M/enz inducers like rifampin etc Keto efficacy.

Limited clinical use for systemic infectionsmucocutaneouscandidiasis, non-meningeal infections eg candida vulvovaginitis,

other deep mycoses etc. Mainly for dermatophytoses since conc

in str corneum. Reserve drug in monilial vaginitis.

Dose : 200-600 mg/d in 1-2 div doses.


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ITRACONAZOLE

Most potent azole, broader spectrum, fungistatic

Avail in oral formulations, well abs orally.

Abs enhanced by fatty meal, low gastric pH. Well distr esp in

vagina, skin & nails. Metab in liver, excr in feces. t1/2 :30-60 hrs.

No effect on mammalian steroids No related S/Es

ADRs : Generally well tolerated, esp in low doses. GIT S/Es,

dizziness, itching, headache, hypokalemia etc. Rarely, rise of se

transaminases.


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Itraconazole (Contd)

Interaxns: Similar to Ketoconazole.

Uses : Drug of choice for Dermatophytosis, Onychomycosis,

and other systemic mycoses like Aspergillosis, non-meningeal

Histoplasma, Chromomycosis, Blastomyces, Coccidioides,

Paracoccidioiodo, Preferred over Keto.

Dose : 100-200 mg/d in 1-2 div doses with food depending

upon indication.

Daily/Pulse therapy (200mg bd for 1wk each month for 3mths) for Onychomycosis.


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FLUCONAZOLE

Water sol triazole, good oral bioavail indep of pH

Well distr in all body fluids incl CSF

Excreted unchanged by kidney. t1/2: 25-30 hrs. Dose in renal

dis. No inh of human steroid synth.

Least interactions with hepatic enzymes, except inhibits metab of

Astemizole, Rifampin, Sulfonylureas, Theophylline, Warfarin.

Other minor ADRs.

Uses : Cryptococcal meningitis (AIDS), Broad spectrum

prophylactic, oropharyngeal candidiasis


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Fluconazole (Contd)

Dose : 100-800 mg/d, depending upon indication.

Vaginal candidiasis150mg single oral dose

Oral candidiasis150mg daily for 14 days.

Tineasis / Cutaneous candidiasis150 mg weekly for 4 wks(12 months for toe-nails).

Disseminated candidiasis / other serious systemic fungal inf200-400mg/d for 1-3 months or even longer.

Also, for fungal keratitis.


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VORICONAZOLE

Most recent triazole

Both IV and oral formulations avail. Well abs orally, metab in

liver.

Effective against fluconazole resistant organisms, esp Candida

(C krusei), Aspergillus.

Dose400 mg/d.

ADRs : Well tolerated. propensity to inhibit human CYP 450

enz. Reversible visual disturbances reported.


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GRISEOFULVIN

Fungistatic agent, actively conc by dermatophytoses

Oral absorptionirregular, but by fatty meal, microfining of

particles. Excr in urine

MOA : Interferes with fungal mitosesmultinucleated &stunted hyphae, abnormal metaphase. Diff from other mitosis

inhibitors.

Gets deposited in newly forming skin, retained in tinea inf cells,inf persists till inf skin shed off.


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Griseofulvin (Contd)

ADRsHeadache, lethargy, confusion, nausea, Heartburn,

leucopenia, enz induction, CNS symptoms, photoallergy,

Allergic reaxns, Disulfiram like (avoid alcohol)

Interaxns: efficacy of warfarin & OCs ( metab), Phenobarb

abs & metab of Griseo trt failure.

UsesDermatophytoses. Systemic azoles / Terbenafine

preferred.

Dose : 125-250 mg QID for 2-6 wks with meals (Skin & Hair

inf) 4-8 wks or more (nails), upto 1 yr for toenails.


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TERBINAFINE

Synth allylamine for oral & topical use

Well abs orally (75%), accumulates in skin, nails, fat. Excr in

urine & feces. t1/2: 11-16 hrs, upto 10 days on repeated dosing.

Inhibits squalene epoxidase sterol squalene toxic

(fungicidal), ergosterol biosynth inhibited

Highly effective for dermatophytoses250 mg OD for 2-6 wks

(skin) and 12 wks (nails), 3-12 months (toe-nails).

efficacious in candidiasis.


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Terbinafine (Contd)

Also avail as 1% cream for topical application.

SEs : Well tolerated. GIT disturbances, dysguesia, rashes,

pruritus, headache, dizziness, arthralgias, myalgias etc. Not

recommended in azotemia, hepatic failure.


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PNEUMOCANDINS

Water soluble, semi-synth lipopeptides

Also called ECHINOCANDINSbased on structure of

Echinocandin-B.

Fungicidal. Inhibits formation of (1,3)-D-Glucan, which

maintains integrity of fungal cell walllysis.

Indications: Azole resistant candida infections, resistant fever

with neutropenia, aspergillosis.

Drugs used : Caspofungin, Micafungin, Amorolfine.


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TOPICAL ANTIFUNGALS

NYSTATIN

A polyene macrolide antibiotic

Mechanism similar to Amphotericin-B

Too toxic for systemic useonly local use

Orally as 5 lakh units TDS for monilial diarrhoea

Topically for oral thrush & vaginal candidiasis (1-5 lac IU

pessaries), monilial vaginitis (1 lac IU vaginal tab).


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HAMYCIN Disc by Hind/ABs in Pune. Similar to Nystatin.

Useful only in Oral thrush, cut candidiasis, monilial &

trichomonas vaginitis, aspergillus otomycosis.

Avail as 4 lac IU vag pessaries/5 lac IU/g oint.

NATAMYCIN

Used as 1% oint in fungal keratitis, as 25-100mg vag tab in

monilial/trichomonas vaginitis.


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CLOTRIMAZOLE & MICONAZOLE

Only topical use as creams / ointments. Well tolerat.

5% systemic abs from skin

Readily penetrates stratum corneum

Fungicidal activity for 3-4 days

Indications : Oral thrush, Dermatophytoses, Otomycosis,Atheletes foot, cut/vag candidiasis. 7 day course recommended.

Clotrimazole1% lotion/cream, 100 mg vag tab.

Miconazole2% gel/oint, 100mg vag ovules.


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TOLNAFTATE

Effective drug for Tinea inf. Also, otomycosis. Used for 1-

3wks. Not useful in candidiasis

Poor skin penetration useful for T/pedis, T/capitis &

Onychomycosis.

Salicylic acid facilitates penetration

1% lotion / ointment

Well tolerated. Efficacy than imidazoles.


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CICLOPIROX OLAMINE Broad spectrum fungicidal drug

Useful for tinea, candida infections, P/versicolor.

Good epidermal penetration. Negligible systemic absorption.

1% cream / lotion

HALOPROGIN

Halogenated phenolic ether

Fungicidal

Broad spectrum


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UNDECYLENIC ACID Fungistatic. Well tolerated.

Used in combination with zinc

Inferior to other drugs

Used for diaper rash, tinea crurisWHITFIELDS OINTMENT

Benzoic acid (fungistatic) + Salicylic acid (kerato-lytic) (2:1)

Indications : Tinea pedis. Trt to be continued till infected stratumcorneum is shed.

Irritation & burning sensation (+).


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OTHER DRUGS

Quiniodochlor: weak antifungal activity against

dermatophytoses, mycosis barbae, P/versicolor etc.

Sodium Thiosulfate: Used as 20% soln, twice a day for

P/versicolor.


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NEWER DRUGS

TriazolesPosaconazole, Ravuconazole.

Drugs to fungal cell wall integrityPradimicin, Nikkomycins.

Fungal protein synth inhibitorsSordarins.

Drugs to host immunity against serious systemic mycoses

GM-CSF (lenograstim / molgramostim)

antifungal pharamcotherapy

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