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 4 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 protein—production 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 β-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 membrane’s integrity. Allylamines inhibit ergosterol synthesis. β-3-glucan synthase inhibitor block the production of the β-(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 17 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 PREGNANCY……Category 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, 61 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 62 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 64 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 65 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