MUNI MED Antifungals (antimycotics) MUDr. Alena Machalová, Ph.D. 1 Lékařská fakulta Masarykovy univerzity Antimycotics ■ Chemotherapeutics for the treatment od infections caused by pathogenic fungi: ■t incidence: immunodefficiencv, DM, radiotherapy, chemotherapy, HIV, transplantations Mycotic infections: ■superficial (local) - skin and mucous membranes ■systemic infections - individuals with weakened immunity (therapy with ATB, CHT, cytostatics,...) Superficial mycoses Dermatomycoses — trychophyton - epidermophyton microsporum dermatophyton (tinea) Superficial candidiasis Skin, nails and mucosae (oral cavity, vagina), infections caused by Candida yeasts (most often Candida albicans). MUNI M E U*-y TINEA (synonymum pro dermatofytózu) lokalizace číselná synonymum dg. Tlnea vlasů a vousů B 35.0 tlnea capltls, tlnea barbae Tlnea ungulum B 35.1 derrnatofytlcká onychomykóza Tlnea manus B 35.2 dermatofytóza postihující dla- ně nebo hřbetnf část ruky Tlnea pedls B 35.3 dermatofytóza nohy Tlnea corporis B 35.4 dermatofytóza postihující kůži trupu, bezvousou část obličeje horní končetiny od ramen k zápěstí a dolní končetiny od trísel ke hleznům Tlnea cruris B 35.6 tlnea Inguinales, dermatofytóza třísel KAM Dl DÓZA Kvasinkové onemocnení sliznice ústní B 37.0 Kvasinkové onemocnení kůže a nehtů B 37.2 JINÉ DERMATOMYKÓZY Pityriasis versicolor Malasezlová fdllkullttda Erythrasma a trichomycosis pal mel II na Keratomycosls B 36.0 nemá vlastní kód byly přeřazeny mezi bakteriální onemocnení dnes označení pro my-kotlckou keratltldu oka M U í J1 ED Dermatophytes Tinea corporis (ringworm), includes tinea gladiátorům and tinea faciei Tinea capitis (ringworm of the scalp) Tinea cruris (jock itch) Tinea pedis (athlete's foot) Tinea unguium (onychomycosis) Tinea manuum (commonly presents with "one-hand, two-feet" involvement) Tinea barbae (beard infection in male adolescents and adults) Tinea incognito (altered appearance of dermatophyte infection caused by topical steroids) Candida (yeast) and mold, which may cause onychomycosis or coexist in a dystrophic nail Pityriasis versicolor (formerly tinea versicolor) caused by Malassezia species Definujte zapat uncommon fungal skin infections that involve other organs (e.g., blastomycosis, sporotrichosis) MUNI MED Systemic mycoses -Lung aspergilosis -Pneumocystis pneumonia (P.carini) -Legionella pneumonia -Cryptocococal meningitis and endocarditis -Rhinocerebral mucomycose - Systemic candidiasis Risk factors for invasive candidiasis Iatrogenic factors > 3 antibiotics > 4 days at ICU > 2 days on ventilator central venous catheter parenteral nutrition abdominal surgery Factors of the patient chronic neutropenia immunosuppression DM colonization by Candida elderly person The most common agents of mycotic infections Yeasts Candida species C.albicans 50-80% C.tropicalis C.krusei C.glabrata C.parapsilosis C.lusitaniae Moulds Aspergillus sp. A.fumigatus 80-90 % A.flavus 10-15 % A.terreus 2-5 % A.niger The treatment of fungal infections -curing deep tissue mycosis is difficult; patient may die even if given modern effective antifungals -treatment may last up to 4-6 weeks -surgical resection of the most affected focus may be required Mechanism of action of antifungals ■ Specific - interfering at a defined place of micromycet metabolism ■ Nonspecific - they usually work also on bacteria and can be considered antifugical antiseptics - Blockage of synthesis fungal lipid (ergosterol) in cell membranes CM, CM, 10 Definujte zápatí - název prezentace / pracoviště Ergosterol MU n I ED ANTIMYCOTICS squalene allylamines squalenepoxidase oxidosqualene i azoles lanosterol - lanosterol-14a -demethylase Ergosterol polyenes 1-3 glukan echinocandins u u H £ I ^ o O < EE 2 hydroxypyridone derrivative ENZYME ACTIVITY REDOX STABILITY GENETIC INFORMATION Ciclopirox Mechanism of action of antifungals Fungal cell Cell membrane and cell wall j- MännOpFotäins ß-(1f6]-gtucan ß-(1.3)-glucEm K - Ergosterol Synthe s rs Pathway Phospholipid btlaycr cell membrane ;í M .-IHjfucari synthase Inhibition Inhibition D NA/RN A Synthesis Squalen e Inhibition -1- Ergosterol 12 Definujte zápatí - název prezentace / pracoviště MUNI ED Classification of antifungals according to the mechanism of action Antifungals -classification by site of action Wall/membrane Intracellular Echinokandins - beta glucan synthesis inhibitors kaspofungin Others Eg. ciklopirox Ergosterol inhibitors Polyenes - ergosterol binding Allylamines -inhibitors of squalen monooxidaase terbinafin Antimetabolites pyrimidine analogues Flucytosin Mitosis inhibitors Griseofulvin Imidazoles * * Azoles - lanosterol 14 alpha-demethylase inhibitors Triazoles Thiazoles M U f| I ED Classification of antifungals Polyenes systemic amphotericin B local nystatin, natamycin Antimetabolites systemic flucytosine Azoles systemic fluconazole, itrakonazole vorikonazole posakonazole local clotrimazole, ekonazole, oxikonazole, terkonazole,... Echinocandines systemic caspofungin, anidulafungin others systemic Alylamines - terbinafin, griseofulvin local ciclopiroxolamin, tolnaftate Polyenes Amphotericin Nystatin B Natamycin MED Systemic polyenes > -Amphotericin B —^m^^^^mmm^^^ ■ broadest spectrum, lowest resistance am**«***«*, 1 Intercalation of cell membrane ■ . Nci toxic, most of patients percieve some grade of toxicity/AE ggggfe, ^ , iH>»ii^rti. ■ ^ t^yiy^ ■ I ■. h^fciMW ^ ClLCAJ Amphmil Toxicity ■ Acute or infusion related toxicity: ■ fever, chills, rigor, nausea, vomiting, ■ tachycardia, hypotension, bronchospasm ■ headache, muscle pain, joint pain, ■ allergies, ■ thrombophlebitis Prevention of toxicity: ■Liposomes - ^nefrotoxicity Chronic or organ toxicity: ■ nephrotoxicity (total dose) followed by electrolyte imbalance, ■ neuropathy -Premedication: ■ normocytic normochromic anemia (therapy: erythropoietin) , ■ trombocytopenia "Hyaratation ■Paracetamol ■Antihistamines ■Cortikosteroids 3 prep: •Amfotericin B lipid complex (Abelcet) ■ Liposomalni'Amfotericin B (Ambisom) ■ Koloiddispersion of amphotericin B (Amphocil) IUIU»'I E D4 >" Lipid Amphotericin B Formulations Abelceta ABLC Amphotec ® ABCD Top v'tzvt of slrajle complex A55rjnm :- i: .■ .- Squafene Accumulation toxic »tflrol* I coll membrane 23 Definujte zápatí - název prezentace / pracoviště Inhibition txf 14-atpha-dom«lhyla&e E rr" Azoles Ketoconazole ■accumulation in the skin (5 days after discontinuation) ■ p.o., skin, hair and nail infections (dermatophytes and yeasts) ■ for the treatment of endogenous Cushing's syndrome Flukonazol ■ p.o. i.v., Nizoral* šampón 2% . nrotl upium "j í am f.l 4MIBM I DIFLUCAN I the only hydrophilic - excretion in urine the highest therapeutic index, the least AE (GIT, allergies, headaches), DDI Great clinical experience, very often used also in children 24 Definujte zápatí - název prezentace / pracoviště MU m I E D Azoles Itraconazole p.o., variable absorption, 1st pass effect, |3-cyclodextrin i.v. high antifungal specificity incl. Aspergillus), does not penetrate into the CNS AE: increased liver enzymes, skin reactions Definujte zápatí - název prezentace / pracoviště Azoles Voriconazole - Better effect in invasive aspergillosis than amphoterecin B - p.o. and i.v., almost complete F (95-96%) - High fungicidal aktivity- Candida, aspergillus - invasive life-threatening infections (aspergillosis, mucormycosis) candidoses rezistant to fluconazole Posaconazole - second-line drug - prohylaxis of candidiasis in risk patients, aspergillosis resistant to AmB or itraconazole, or in intolerance of 1st line drugs I Léčivý přípravek obsahující posakonszol aktuálně dostupný v Cft 26 Definujte zápatí - název prezentace / pracoviště MU M I M E DV Topical (local) azoles 1 — Clotrimazole (depot in stratum corneum) - Econazole (also efficient against some bacterias) -Oxiconazole, Fenticonazole, Tioconazole Dermacologics and gynecologies, are not absorbed AE: irritation, contact allergies 27 Definujte zápatí - název prezentace / pracoviště MU MI Allylamines Terbinafine terbinafin ANTIMYCOTICS squalene allylamines squalenepoxidase oxidosqualene i azoles lanosterol - lanosterol-14a -demethylase Ergosterol polyenes 1-3 glukan echinocandins u u H £ I ^ o O < EE 2 hydroxypyridone derrivative ENZYME ACTIVITY REDOX STABILITY GENETIC INFORMATION Ciclopirox Allylamines Terbinafine MoA: block of squalenepoxidase — acummulation in the adipose tissue and skin - fungicidal activity up to 3 w after discont. (synergistic effect with azoles) AE: dyspepsia, loss of apetite I: tinea, candidiasis, onychomycosis MS EXDEfierpI' Mi Echinocandins = lipopeptides MoA: inhibition of glucan synthesis (cell wall component of many fungi and yeasts) - parenteral administration - synergism when combined with azoles or polyenes - not metabolized via CYP AE: minimal toxicity, flebitis, GIT AE, hypokalemia 4 Echinocandins = lipopeptides -Caspofungin (Cancidas) - Micafungin (Mycamine) - Anidulafungin (Ecalta) I: alternative therapies for severe invasive mycoses (aspergillosis, invasive candidiasis) 1st choice in hemodynamic instable patient with severe infection M U ft! I Other antifungal drugs Ciklopirox(-olamin) Tolnaftate (Griseofungin) MUNI ED MUNI Ciclopirox-olamine MED topical fungicidal antimycotic agent + G+/G- bacteria, mycoplasms, trichomonades MoA: chelates Fe3+(^ metaloproteins function abruption) ^ i. cytochrome - blocks energy metabolism of the mycotic cell ^ inh. catalase, peroxidase - block antioxidative protection Cytoplasmatic membrane - block of transporters - deplete essent. AA (Leu), nucleotides,.. antioxidant - scavenger ROS (OH») inhibitor AA ^ inh. synthesis a LT in human PMN cells antiinflammatory activity in vivo MUNI MED Tolnaftate OTC drug for the treatment of tinea pedis, tinea cruris, dermatophytosis Fungicid MoA similar to terbinafine MUNI MED Griseofulvin obsolent Narrow spectrum, fungistatic MA: interaction with microtubules - mitotic poison • administered orally • acummulation in stratum corneum, hair, nails • I: dermatomycoses AE: GIT irritation, alergy, leucopenia, hepatotoxicity, nerologic disorders CYP inducer UNI Nonspecific antifungals ANTIMYCOTICS 1) Acids and derivatives: Ac. salicylicum Ac. boricum Ac. undecylenicum Ac. benzoicum 2) Phenols: resorcinol, hexachlorophene H.C- i -N, ci- H3C'W 1 N. 3) Organic dyes: • crystal gentian - (Methylrosanilinii chloridům) • methylene blue - (Methylthioninii chloridům) • brilliant green - (Viride nitens) v -CH, H3C MUNI ANTIMYCOTICS MED Nonspecific antifungals 4) Aldehydes: formaldehyde, glutaraldehyde 5) Halogens and derivatives: iodine, iodine-povidon, iodine-glycerol chlorine 6) Oxidizing agents: KMn04, H202 (1-3%) 7) Tars: Lithanthracis pix Betulae pix Fagi pix...