CHEMOTHERAPY

ANTIFUNGAL DRUGS

ANTI FUNGAL DRUGS

For superficial & deep fungal infections. Dermatophytoses a 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).

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, Cyclopirox olamine, Undecylenic acid.
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AMPHOTERICIN - B
A water insoluble polyene macrolide antibiotic PKs Very poor oral abs, widely distributed, poor CSF entry, no dosage adjustments needed in renal / hepatic dysfunction. MOA Binds 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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AMPHOTERICIN B (Contd)
Antifungal spectrum Candida, 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 IV infusion over 4-8 hrs. Can be sed to 0.7 mg/kg. Oral dose 50-100 mg QID for int monilia. Newer preparations : (a) Amphotericin-B Lipid Complex (ABLC) 35% in ribbon like particles of dimyristoyl PLs (b) Amphotericin-B Colloidal Dispersion (ABCD) 50% drug + cholesteryl sulfate as disc shaped particles.
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AMPHOTERICIN B (Contd)
(c) Liposomal Amphotericin-B [Small unilamellar Vesicles (SUV)] 10% AMB in lecithin liposomes better tolerated drug, better delivery.

Clinical uses : Topical Oral, vaginal & cutaneous candidiasis. Systemic Cryptococcosis, 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.

FLUCYTOSINE
Pyrimidine anti-metabolite Oral formulations available

Inhibits DNA & RNA synth, after getting conv to 5-FU5f/deoxyuridylic acidinh of thymidylate synth. Selective. Mammals conv into active metab Synergistic action with Amphotericin-B
Well distributed, incl CSF. Elimination primarily renal

ADRs BM suppression, enterocolitis

Uses Cryptococcal & Candida infections, Dose : 100-150 mg/kg/d in 4 div doses.
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AZOLES
Imidazoles Ketoconazole, Miconazole, Clotrimazole, Econazole

Triazoles Itraconazole, Fluconazole.

MOAInh fungal lanosterol 14-demethylase reduced ergosterol synthesis accumulation of 14 methyl sterols membrane abnormalities in fungus fungicidal / fungistatic. Selective, since affinity for mammalian CYP 450 enzymes.

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, mild hepatotoxicity. - 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 infections mucocutaneous candidiasis, 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 3 mths) 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, Sulfonyl ureas, 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 candidiasis 150mg single oral dose Oral candidiasis 150mg daily for 14 days. Tineasis / Cutaneous candidiasis 150 mg weekly for 4 wks (12 months for toe-nails). Disseminated candidiasis / other serious systemic fungal inf 200-400mg/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. Dose 400 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 absorption irregular, but by fatty meal, microfining of particles. Excr in urine MOA : Interferes with fungal mitoses multinucleated & 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)
ADRs Headache, 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. Uses Dermatophytoses. 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 dermatophytoses 250 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 ECHINOCANDINS based 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 use only 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.

Clotrimazole 1% lotion/cream, 100 mg vag tab. Miconazole 2% gel/oint, 100mg vag ovules.
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TOLNAFTATE
Effective drug for Tinea inf. Also, otomycosis. Used for 13wks. 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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 Broad spectrum fungicidal drug

CICLOPIROX OLAMINE

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 cruris WHITFIELDS OINTMENT Benzoic acid (fungistatic) + Salicylic acid (kerato-lytic) (2:1) Indications : Tinea pedis. Trt to be continued till infected stratum corneum 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
Triazoles Posaconazole, Ravuconazole. Drugs to fungal cell wall integrity Pradimicin, Nikkomycins. Fungal protein synth inhibitors Sordarins. Drugs to host immunity against serious systemic mycoses GM-CSF (lenograstim / molgramostim)

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