ANTIFUNGAL DRUGS

FUNGAL INFECTION IN HUMANS = MYCOSIS

Major Types of Mycoses

superficial cutaneous subcutaneous systemic opportunistic

Symptoms vary from cosmetic to life threatening

FUNGAL INFECTIONS
Superficial mycoses hair, skin, mucous
membranes eg dermatophytosis (ringworm), candida (thrush, intertrigo) and malassezia furfur (pityriasis versicolor)

Subcutaneous mycoses dermis, subcut and

adjacent bones eg mycetoma, chromoblastomycosis, sporotrichosis

Systemic mycoses
1.

2.

Inhalation =>pulmonary infection=>disseminated (eg histoplasmosis, coccidioidomycosis, blastomycosis) Opportunist aspergillus, candida, crytococcus.

FUNGAL INFECTIONS

Incidence

; increasing trend Slow onset Difficult to diagnose & eradicate Long duration of therapy

BACKGROUND - FUNGI
3 main groups:

Moulds reproduce by spores, which may produce

mycotoxins

Yeasts grow by budding, ferment sugars

Dimorphic fungi capable of changing growth

FACTS ON FUNGI

Fungal cell membranes have a unique sterol, ergosterol, which replaces cholesterol found in mammalian cell membranes Tubule proteinproduction of a different type in microtubules formed during nuclear division.

Chitin biosynthesis occurs in fungi. Most fungi have very small nuclei, with little repetitive DNA.
Mitosis is generally accomplished without dissolution of the nuclear envelope.

FUNGAL CELL

BACKGROUND - FUNGI
May be: = pathogenic in all exposed patients (eg histoplasma capsulatum, coccidioides immitis) = opportunists (eg candida, aspergillus) = or cause illness via mycotoxins or allergic reaction after inhalation of spores

FUNGAL INFECTIONS
Risks:

= Exposure (living conditions, occupation and

leisure activities), animal contact, warm

climates, geography
= AIDS

= Immunosupression (transplant)
= Broad spectrum antibiotics

FUNGAL INFECTIONS

SYSTEMIC HISTOPLASMOSIS ASPERGILLOSIS CRYPTOCOCCOSI S BLASTOMYCOSIS MUCORMYCOSIS CANDIDIASIS

LOCAL DERMATOPHYTOS IS SPOROTRICHIOSI S ZYGOMYCOSIS CHROMOMYCOSIS RHINOSPOIDIOSIS

COMMON FUNGAL INFECTIONS

Pityriasis versicolor Candidiasis : intertrigo, paronychia , stomatitis, vulvovaginitis Tinea: corpis, cruris, barbae, capitis, pedis, manum, unguium

Histoplasmosis coccidoiomycosis blastomycosis cryptococcosis aspergillosis mucormicosis mycetoma

CLASSIFICATION IN GENEMEDRX
Antifungals
Polyenes Imidazoles Triazole -3-glucan Allylamines synthase inhibitors
naftifine caspofungin

Other

nystatin

miconazole

fluconazole

griseofulvin

amphotericin B

clotrimazole

itraconazole terbinafine

micafungin

flucytosine

ketoconazole

voriconazole butenafine

anidulafungin

tolnaftate

posaconazole

ANTIFUNGAL AGENTS
HOW DO THEY WORK?
Polyenes, triazoles, and imidazoles target ergosterol destroying the cell membranes integrity. Allylamines inhibit ergosterol synthesis. -3-glucan synthase inhibitor block the production of the -(1,3)-glucan protein damaging the cell wall. Every component of the cell wall and membrane can be targeted. Drugs not available in the market such as Nikkomycin and Polyoxin target chitin synthase. Mannoproteins are another potential target.
Image from http://www.doctorfungus.org/thedrugs/antif_pharm.htm

Other antifungals such as flucytosine inhibit DNA/RNA synthesis and griseofulvin inhibit fungal cell mitosis preventing cell proliferation and function.

ERGOSTEROL SYNTHESIS PATHWAY &

SITE OF ACTION OF ANTIFUNGAL DRUGS

Squalene ] ] squalene epoxidase === inhibit (Terbinafine, Butenafine,Tolnaftate) ] Squalene 2, 3-epoxide ] ] Lanosterol ] ] ===Azoles ] 4, 14 dimethylzymosterol [ [________________>Zymosterol--------------ERGOSTEROL

WHY IS THIS IMPORTANT?

36% of drugs are metabolized by CYP 3A4 and antifungals are largely 3A4 inhibitors Antifungals can effect up to 60% of all drugs due to inhibition of 3A4, 2C9, 2C19, 1A2.

Image from http://www.doctorfungus.org/thedrugs/antif_pharm.htm

ANTIFUNGAL AGENTS

SYSTEMIC ANTIFUNGALS
TOPICAL ANTIFUNGALS

Some are fungistatic, while others are fungicidal

PATKI

SYSTEMIC ANTIFUNGALS 1. 2. 3. 4. 5. GRISEOFULVIN AMPHOTERICIN- B FLUCYTOSINE IMIDAZOLES TRIAZOLES

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GRISEOFLFULVIN

A heterocyclic benzofuran antibiotic Most commonly used for fungal infections of skin caused by dermatophytes
It is derived from the mold Penicillium griseofulvum

MOA==Fungistatic drug interfere with mitosis to form multinucleated, stunted, & curled hyphae (hence called the curling factor)

INDICATIONS
Tinea capitis Tinea pedis & tinea manuum(optional) Tinea corporis that is either

Widespread, or Has underlying predisposing factor like DM, HIV, Immunosuppresive therapy Is not responding to topical antifungals

Tinea unguium: however newer oral antifungals like Terbinafine & Itraconazole are preferred b/c of higher efficacy in nail infections

GRISEOFLFULVIN

DOSE
250mg twice a day (micronized) or 375mg once a day (ultramicronized) for an ordinary adult
10mg/kg/day (micronized) for children PREGNANCYCategory C

DURATION OF GRISEOFULVIN THERAPY DERMATOPHYTOSIS

IN

Body skin Hair Palms & soles Finger nails Toe nails

4 weeks 4-6 weeks 6-8 weeks 6-12 months 12-18 months

ADVERSE EFFECTS

Systemic Headache (commonest) GIT disturbances Transient leukopenia Peripheral neuritis Albuminuria (without renal damage) Cutaneous Fixed drug eruptions, photoallergic dermatitis, & lichenoid drug eruption Precipitation of acute intermittent porphyria or lupus erythematosus

KEY POINTS

Duration of treatment depends upon the site of infection, thickness of SC, its turnover rate, & immunological status Since it is fungistatic drug, fungus persists in already infected keratin till it is shed off Ineffective against pityrosporum, candidal, molds, & deep mycotic infections

KEY POINTS

Griseofulvin can cause alcohol intolerance Reduces efficacy of oral contraceptive pills

Absorption of griseofulvin depends upon the particle size & presence of fat in the food.
Phenobarbitone reduces the absorption.

FLUCONAZOLE
Broad-spectrum triazole antifungal; It is also somewhat effective against some Gram-positive & anaerobic bacteria

MOA==Fungicidal drug, inhibits fungal ergosterol synthesis by blocking fungal enzyme lanosterol 14-demethylase.

Mechanism of antibacterial action remains unexplained

FLUCONAZOLE

Cryptococcal meningitis & coccidioidal meningitis Disseminated candidiasis Candidiasis including oropharyngeal, vaginal, & mucocutaneous (except C. krusei) Histoplasmosis, paracoccidiodomycosis, & sporotrichosis Pityrosporum ovale infections Fungal keratitis Dermatophyte infections of the skin, hair, & nail

DOSES & DURATION

Dermatophyte & cutaneous candidiasis Vaginal candidiasis & candidial balanoposthitis

150mg/wk for 4-6 week

150mg single dose or repeat for 3 weeks in cases off recurrences or uncorrectable predisposing factor 400 mg stat (repeat after 2 weeks)

Pityriasis versicolor

DOSES & DURATION

Cryptococcosis

400mg OD for 8-10 weeks in non-AIDS pts. In AIDS patients, 200mg OD (suppressive dose) after i.v. amphotericin B + flucytosine (5-FC) 150 mg/wk till cure (not more than 1 year)

Onychomycosis

FLUCONAZOLE

Systemic: Well tolerated; side effects may occur like nausea, vomiting, abdominal pain, headache, thrombocytopenia, & raised creatinine levels. Cutaneous: Maculopapular rash (rare) Pregnancy=== Category C

KEY POINTS

Of the orally administered fluconazole 94% is absorbed; Oral bioavailability is not affected by food or gastric pH; 80% of drug is excreted unchanged in urine. Longer half life (25-30h) permits its single dose & once weekly regimen Penetration in brain & CSF is good, hence used for cryptococcal meningitis

KEY POINTS

Unlike ketoconazole, it does not inhibit steroid synthesis & hence is not antiandrogenic (no gynecomastia) Plasma levels of drug is reduced by rifampicin & enhanced by zidovudine Fluconazole potentiates hypoglycemic effects of tolbutamide & glipizide. Can cause elevation of hepatic transaminases in HIV pts (due to high doses for prolong period)

ITRACONAZOLE

Broad-spectrum antifungal with fungistatic action that also includes Aspergillus & Mucor MOA=== Inhibits fungal ergosterol synthesis like other azoles

ITRACONAZOLE

Subcutaneous mycoses like eumycetoma & chromoblastomycosis (DOC) Systemic mycoses not associated with meningitis like blastomycosis & paracoccidiomycosis (DOC)

Aspergillosis & mucormycosis (partially effective & 2nd DOC)

ITRACONAZOLE

Pityrosporum ovale infections

Dermatophyte infections of the skin, hair, and nail Candidiasis

Dose== 200mg OD / BD , 3-5mg/kg OD

DOSES & DURATION IN SUPERFICIAL FUNGAL INFECTIONS

Dermatophytosis

5mg/kg/day x 2-4 week 100mg daily for 4 weeks tinea pedis/manuum 600mg single dose 100mg daily for 15 days 1000 mg stat

Vaginal candidiasis Oral candidiasis Pityriasis versicolor

DOSES & DURATION

Finger nail onychomycosis

200 mg BD for 7 consecutive days/per month x 2 months 200 mg BD for 7 consecutive days/per month x 3 months

Toe nail onychomycosis

Seborrhec dermatitis (experimental indication)

200 mg daily for 7 days

ADVERSE EFFECTS

Systemic: More side effects as compared to fluconazole, nausea, dizziness, headache, abdominal pain, constipation, hypokalemia, & impotence. Cutaneous: skin rash & cutaneous vasculitis

Pregnancy=== Category C

DRUG INTERACTIONS

Phenytoin , rifampicin, H2 blockers decrease plasma concentration of drug. Increases concentration of cyclosporine & warfarin. Itraconazole & statins can lead to rhabdomyolysis. Itraconazole and terfenadine, astemizole, cisapride can cause ventricular tachycardia. Itraconazole & nifedipine: peripheral edema.

KEY POINTS

Oral absorption is enhanced by food or gastric pH. Penetration of drug in brain & CSF is poor. Half-life = 24-42 hrs Unlike ketoconazole, it does not inhibit steroid synthesis & hence does not have antiandrogenic effects like gynecomastia,
loss of libido or oligospermia.

Drug may persist in stratum corneum for 3-4 weeks after discontinuation justifying pulse therapy of itraconazole.

KETOCONAZOLE

First oral broad-spectrum antifungal with mechanism of action similar to that of other azoles.

Dose== 200mg OD/ BD , 3-6mg/kg OD Conaz 200mg tab, NIZRAL 2% cream, NIZRAL 2% shampoo

DRUG INTERACTIONS

H2 blockers, proton pump inhibitors, & antacids decrease oral absorption. Phenytoin & rifampicin drecrease plasma concentration of ketoconazole. Ketoconazole increases concentration of cyclosporine & warfarin, sulfonyureas.

ADVERSE EFFECTS
SYSTEMIC

CUTANEOUS

Nausea & vomiting (most common) Anorexia Headache Paresthesia Antiandrogenic effects
(loss of libido, gynecomastia, hair loss, oligospermia)

Rash Alopecia

KEY POINTS

Oral absorption is enhanced by gastric acid. Penetration in brain & CSF is poor. Half-life = 7-10 hrs Ketoconazole is not a preferred drug for fungal infections b/c of its antiandrogenic effects & potential drug interactions. But still can be used for candidial, dermatophyte, & pityrosporum infections for short period of time.

TERBINAFINE

Oral & topical broad-spectrum allylamine antifungal. MOA=== Inhibits the squalene epoxidase, leading to accumulation of intrcellular squalene & deficient ergosterol synthesis with subseqent fungal cell death. Drug reaches the body surface through diffusion from dermal vasculature and via sebum to the hair follicle.

TERBINAFINE

Widespread dermatophytosis (as an effective alternative to griseofulvin). Candidiasis (less effective than other alternative anticandidial drugs like fluconazole). Adult 250mg OD , Children <20kg : 62.5 mg/day in divided doses, QID Children >20kg : 125 mg/day in divided doses, QID Pregnancy== Category B

DOSES & DURATION

Dermatophytosis

250mg daily for 2-4 weeks=tinea corporis/tinea cruris 250mg daily for 4-6 wks=tinea pedis 250mg daily for 4-6 wks=tinea capitis

Cutaneous candidiasis (not routinely recommended)

250 mg once daily for 2-4 weeks

DOSES & DURATION

Finger nail onychomycosis

200mg OD for 6 weeks-3 month 200mg BD for 7 consecutive days/per month x 2 months

Toe nail onychomycosis

200mg OD for 6 weeks-3 month 200mg BD for 7 consecutive days/per month x 3 months

ADVERSE EFFECTS
SYSTEMIC

CUTANEOUS

Mild gastrointestinal distrabances Dreanged hepatic & renal function

Skin rash Autoimmune hepatitis Precipitation of lupus erythematosus Acute exanthematous pustulosis & dyschromatosis are also reported

KEY POINTS

70-80% oral absorption, not significantly affected by presence of food. Being liphophilic, it accumulates in keratinous tissues & is present in the tissues long after it is withdrawn. This is the basis of terbinafine pulse therapy. Less effective against candida & pityrosporum infections particularly when used topically. Rifampicin increases elimination of terbinafine.

AMPHOTERICIN B (AMB)

Broad-spectrum polyene macrolide antibiotic is the most potent antifungal agent for systemic mycosis. Fungicidal drug at higher concentrations & static at lower levels. MOA=== High affinity for fungal ergosterol, forms micropore in fungal cell membrane through which ions, amino acids, & other water soluble substances move out. Markedly increases cell permeability. Cholestrol, present in host cell membranes, closely resembles fungal ergosterol & thus explains the high toxicity of AMB in humans.

AMPHOTERICIN B (AMB)

Disseminated candidiasis, cryptococcosis, & coccidioidomycosis (in combination with 5-FC) Histoplasmosis (in combination with itraconazole or ketoconazole) Aspergillosis & mucor mycosis (DOC) Disseminated sporotrichosis Chromoblastomycosis Paracoccidioidomycosis (2nd DOC) Leishmaniasis (reserve drug)

AMPHOTERICIN B (AMB)

0.4 -0.6 mg/kg OD for 6-12 weeks (available in powdered form to be dissolved in 5% dextrose) Pregnancy== Category B

LIPOSOMAL AMB

New lipid formulations (DOSE: 3-5mg/kg/day) AMB is incorporated into lipid formulations to reduce toxicity & enhance efficacy. This allows higher dose to be used without increasing the toxicity. Much more expensive than ordinary AMB. Currently three such formulations are avilable: AmBisome incorporates AMB with liposomes Abelact - ribbons of lipids interspersed with AMB Amphocil AMB colloidal suspension

ADVERSE EFFECTS
SYSTEMIC

CUTANEOUS

Nephrotixicity -most serious

(dose>5mg/day may produce irreversible renal damage)

Hypersensitivity

Nausea & vomiting Fever & chills Hypokalemia Thrombophlebitis Thrombocytopenia Anaphylaaxis

KEY POINTS

AMB is not absorbed enterally; hence can be given orally for intestinal candidiasis. Drug concentration achieved in infected skin is very low, & hence ineffective against superficial fungal infections. Penetration in brain & CSF is poor (but extremely effective in fungal meningitis when combined with 5-FC)

Drug should be preferably given through CVP line due to risk of thrombophlebitis.

KEY POINTS

Antihistamines & IV Hydrocortisone 100mg is routinely given prior to the administration of AMB to avoid hypersensitivity reactions. IV or oral K+ supplementation is necessary with monitoring of serum potasium levels. Daily monitoring of BUN & Crt is mandatory. Start with test dose of 1mg on day 1. If there is no hypersensitivity, increase to 0.5mg/kg/day. If no other side effects, the dose can be steadily increased (except in candidiasis) to reach a maximum of 1mg/kg/day For serious infections, one can dispense with the test dose & start with higher dose.

FLUCYTOSINE (5-FC)

Pyrimidine antimetabolite, narrow-spectrum fungistatic

MOA=== It is taken up by fungal cells and converted into 5-fluorouricil & then 5-fluorodeoxyuridylic acid, which is an inhibitor of thymidylate synthesis. Spectrum Cryptococcus neoformans, strains causing chromoblastomycosis, a few species of Candida & Aspergillus.

FLUCYTOSINE (5-FC)

Indications Chromoblastomycosis Meningeal & nonmeningeal cryptococcosis and disseminated candidiasis (synergistic action with AMB)

Dose 100-150 mg/kg/day in four divided doses orally Pregnancy== Category B

FLUCYTOSINE (5-FC)

Adverse Effects Mylosuppression GI disturbances Mild & reversible liver dysfunction

KEY POINTS

Since this is a narrow-spectrum fungistatic, it is mainly used as an adjuvant drug & not used as a sole therapy. CSF penetration is excellent, hence it is combined with AMB in fungal meningitis. Mammalian bone marrow cell have the capacity to convert 5-FC to 5-FU, and this explains marrow toxicity with flucytosine. Concurrent use of other mylosuppressive drugs should be avoided.

PATKI

TOPICAL ANTIFUNGAL

AZOLES -

CLOTRIMAZOLE,ECONAZOLE, MICONAZOLE,TERCONAZOLE .BUTOCONAZOLE CICLOPIROX OLAMINE HALOPROGIN,BENZOIC+SALICYLI C, TOLNAFTATE,TERBINAFINE, NYSTATIN UNDECYLENIC ACID,
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PATKI

CLOTRIMAZOLE
fungicidal,1% cream,lotion,vaginal cream 100 mg -vaginal tab-o.d-7 days cure for dermatophytes ,vulvovaginitis, cut.candidiasis-80% success ADRs-erythema,pruritis,burning sensations

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MICONAZOLE Cream,powder,lotion ,100mg Pessaries, Teniasis,vulvovaginitis,80% Success. Terconazole Butoconazole-

CICLOPIROX OLAMINE, HALOPROGIN , TOLNAFTATETRICHOPHYTONS AND MICROSPORUM. TERBINAFINE CREAM

LOCAL ANTIFUNGALS

PATKI

NYSTATIN

similar to amphotericin B used topically and for GI use used against candida and dermatophytes (Epidermophyton, Trichophyton, Microsporum).

Useful Only For Candidiasis- cutanious, Oral Or Vaginal 100,000 Units/Gm Cream,powder. Vaginal Tab-twice A Day-2weeks

ADRs- RARE
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PATKI

OLDER LOCAL ANTIFUNGALS

BENZOIC ACID 6% &SALICYLIC ACID 3%WHITFIELD OINTMENT-TINEA PEDIS. KERTOLYTIC TOO,

POTASSIUM IODIDE-1 GM/MLCUTANIOUS SPOROTRICHIOSIS

GENTIAN VOILET, IODINE, SULPHUR
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ALTERNATIVES

Research conducted in 1996 indicated that the following substances or essential oils had antifungal properties:[12] Allicin - created from crushing garlic Tea tree oil - ISO 4730 ("Oil of Melaleuca, Terpinen-4-ol type") Citronella oil - obtained from the leaves and stems of different species of Cymbopogon (Lemon grass) Iodine - Lugol's iodine olive leaf orange oil palmarosa oil patchouli lemon myrtle Neem Seed Oil Coconut Oil - medium chain triglycerides in the oil have antifungal activities Zinc - in dietary supplements or natural food sources, including pumpkin seeds and chick peas Selenium - in dietary supplements or natural food sources, particularly Brazil nuts Horopito (Pseudowintera colorata) leaf - contains the anti-fungal compound polygodial[5] Israeli researchers at Tel Aviv University's Department of Plant Sciences published a study in 2009 indicating that carnivorous plants like the Venus flytrap contain compounds that may be useful in providing a new class of anti-fungal drugs for use in humans, for fungal infections that are resistant to current anti-fungal drugs

ANY QUESTION ??

Thank

you