Farmaci antifunginei

1. Farmaci antifunginei Un fungo è un organismo appartenente alla famiglia degli eucarioti quali la famiglia dei lieviti, muffe ed i caratteristici funghi edili e tossici Funghi patogeni per l‘uomo 1] Dermatophytes Microsporum, Epidermophyton e Trichophyton 2] Candida 3] Aspergillus 4] Cryptococcus 5] Rhizopus ... Microsporum canis Candida albicans

3. Aspergillus fumigatus is a saprophytic fungus that plays an essential role in recycling environmental carbon and nitrogen. It sporulates abundantly, with every conidial head producing thousands of conidia. The conidia released into the atmosphere have a diameter small enough (2 to 3 mm) to reach the lung alveoli. A. fumigatus does not have an elaborate mechanism for releasing its conidia into the air. Over the past 10 years, A. fumigatus has become the most prevalent airborne fungal pathogen, causing severe and usually fatal invasive infections in immunocompromised hosts in developed countries.

4. For most patients, the main portal of entry and site of infection for A. fumigatus is the respiratory tract. Sites of infections have been described in the normal or immunocompromised host, such as the skin, peritoneum, kidneys, bones, eyes, and gastrointestinal tract. At present, only AmB and itraconazole are available to treat aspergillosis. In spite of their activity in vitro, the efficacy of these drugs in vivo against A. fumigatus remains low, and as a consequence, mortality from IA remains high. Detection of galactomannan in bronchoalveolar lavage fluid seems to be a promising tool for rapid diagnosis in the critical care setting.

8. CATHETER-RELATED BLOODSTREAM INFECTIONS AND CANDIDA BIOFILMS Candida species are the fourth leading cause of health care-associated infections and the third most common cause of central line-associated bloodstream infections.  Candida species are associated with the highest overall crude mortality of all nosocomial bloodstream infections, comparable to that of Pseudomonas and exceeding that of Staphylococcus aureus infections. Candida albicans is the most common fungal species associated with biofilm-related infections. In addition to device- and catheter-related infections, endocarditis and other prosthetic infections have also been associated with biofilm formation. In patients with candidemia, biofilm-producing strains of Candida species have been associated with increased morbidity and mortality compared to non-biofilm-producing strains.

11. http://nedo.gumed.edu.pl/wszpziu/skrypty/Atlas%20Dermatol/I_Derma/000IM02.pdfhttp://nedo.gumed.edu.pl/wszpziu/skrypty/Atlas%20Dermatol/I_Derma/000IM02.pdf Infezioni cutanee da funghi Microsporum canis (Tinea capitis) Trichophyton mentagrophytes

12. Tinea corporis Tinea faciei Tinea cruris

13. Candidiosi, Stomatite, Mughetto Intertrigine da candida (ascelle) Candidiosi da pannolino

14. Oncimicosi

19. Farmaci antifunginei suddivisi per classi • POLIENI • Amphotericina B, Nistatina • AZOLI • Imidazoles: Ketoconazolo.. • Triazoles: Fluconazolo, itraconazolo, voriconazolo, posaconazolo, ravuconazolo • ALLILAMMINE • Terbinafina, butenafina • MORFOLINE • Amorolfine • PIRIMIDINE FLUORINATE Flucitosina

20. Farmaci antifunginei suddivisi per classi ECHINOCANDINE Caspofungin, anidulafungin, micafungin PEPTIDE-NUCLEOSIDE Nikkomicina Z DERIVATITETRAIDROFURANICI Sordarine, azasordarine ALTRI Griseofulvina

21. Nature Reviews Drug Discovery | AOP, published online 20 August 2010; doi:10.1038/nrd3074

23. MECCANISMO DI AZIONE 7] Inibitori della sintesi proteica Sordarine, azasordarine 1] Agenti che interferiscono con l ‘ integrita’della membrana Amphotericina B, Nistatina 2] Inibitori della sintesi dell ‘ ergosterolo Azoli, allilamine, morfoline 3] Inibitori degli acidi nucleici Flucitosina 4] Antimitotici Griseofulvina 5] Inibitori della sintesi del glucano Echinocandine 6] Inibitori della sintesi della chitina Nikkomicina

24. Topical azoles Topical allylamines Other topical antifungals

25. AMFOTERICINA B genera dei pori nella membrana Usi terapeutici : - Leishemaniosi mucocutanea americana - Aspergillosi invasiva - Blastomicosi - Candidiosi ( E’ presente per il 60% nei pazienti affetti da HIV e in più dell’80% in sogggetti con AIDS.) - Meningite criptococcica in pazienti con HIV - Criptococcosi polmonare - Infezioni funginee del SNC

26. Effetti collaterali Amfotericina B Effetti collaterali generali : Perdita di peso corporeo Diarrea, indigestione, perdita dell’appetito, nausea, vomito Febbre, mal di testa Effetti collaterali gravi : Aritmia cardiaca, ipotensione tromboflebiti Ipocaliemia Anafilassi Nefrotossicità convulsioni

27. In addition to infusion-related adverse effects, Amphotericin B ( AmB) may be associated with considerable cumulative toxicity like cardiotoxicity, neurotoxicity and, most notably, nephrotoxicity (60–80% of patients), the latter manifesting in tubular injury and a poorly understood renal vasoconstriction. Although AmB’s nephrotoxic effects are to a certain extent preventable (e.g. by sodium supplementation) and reversible, they represent the main dose-limiting determinants. Fortunately, all approved lipid-based formulations were shown to significantly reduce t he likelihood of severe azotaemia compared to conventional D-AmB, even in patients treated concomitantly with other nephrotoxic drugs. Thus, in many hospitals, conventional D-AmB, despite its lower cost, is largely abandoned as a therapeutic agent against IA . Despite its unfavourable safety profile, AmB still represents the best proven and most important therapeutic option in salvage situations and in the management of breakthrough infections.

28. Treatment and follow-up Treatment regimen consisted of griseofulvin at the dose of 15 mg/kg/d for 6-12 weeks, associated with antifungal topicals for all infants except five (less than 6 months of age), which were treated just by antifungal topicals. The tolerance of treatment was excellent and no side effects or abnormal results in blood chemistry tests were observed. The follow-up in 30 infants showed complete hair re-growth in 28 cases; 2 cases of kerion showed persistent alopecia.

29. GRISEOFULVINA Meccanismo di azione GF is known to inhibit the growth of fungal, plant and mammalian cells mainly by inducing abnormal mitosis and blocking the cells at G2/M phase of cell cycle. Farmacocinetica The antifungal agent griseofulvin is also poorly water soluble drug, and its absorption from oral route is also poor, as a result, failure in providing effective plasma drug profile on conventional oral administration. Interazione tra farmaci Griseofulvin has long been a concern in its interaction with anticoagulants, hormone replacement therapy agents, sedatives, and anticonvulsants.

31. Case report

32. Ketoconazolo Lo Squalene è il precursore di tutte le famiglie di steroidi

33. Classification of triazoles First generation of triazoles • Fluconazole • Itraconazole Second generation of triazoles • Voriconazole • Posaconazole • Ravuconazole

34. Fluconazole was discovered by Richardson et al. working at Pfizer in Sandwich, UK in a programme initiated in 1978. The original patent covering its structure had been filed by Riley and colleagues at ICI Pharmaceuticals, who discontinued antifungal research prior to fluconazole’s launch. Fluconazole was identified because of its in vivo activity, and only many years later were in vitro systems found to measure in vitro activity. Phase 2 studies commenced in 1988 and were focused on Candida, cryptococcal and coccidioidal infections, initially using doses of 50 mg daily.3–6 Prophylaxis studies in neutropenia followed. The increasing need for orally active azoles because of the AIDS epidemic, and respectable efficacy despite low doses of the drug, led to rapid Foods and Drugs Administration and European licensures in 1990.

35. Meccanismo di azione Il ketoconazolo può essere micostatico o fungicida a seconda delle dosi. Inibisce la sintesi dell’ergosterolo che porta come risultato il danno della membrana cellulare con fuoriscita degli elementi intracellulari necessari per la vita del fungo. Inibisce la sintesi dei trigliceridi e dei fosfolipidi dei funghi. Il fluconazolo è un inibitore del CYP450 umanoparticolarmentedegliisoenzimiCYP2C9 e CYP3A4.

37. Fluconazole: Fluconazole is an oral and parenteral agent. It readily penetrates into tissues due to its low lipophilic nature and limited protein binding; it is approximately 90% bioavailable. Concentrations in urine are several fold greater than in blood (10- to 20-fold greater) (11,12). Rare, but serious,hepatotoxicity may be associated with fluconazole. Drug interactions are possible because fluconazole is an inducer of cytochrome P450 isoenzymes. Clinical use in paediatrics: Fluconazole, the azole that is most widely used in paediatrics, is often used in the treatment of Candida and cryptococcal infections. It is more active against Candida albicans compared with other candidial strains (eg, Candida parapsilosis, Candida glabrata, Candida krusei and Candida tropicalis).

38. TRIAZOLI Voriconazole Voriconazole (VRC) is a triazole antifungal agent, which demonstrated good activity against Aspergillus strains, even when resistant to AmB and itraconazole (ITC). As is the case for all triazole antifungal agents, VRC inhibits the fungal enzyme 14 alfa-lanosterol demethylase, which catalyses a key step in the membrane synthesis, namely the conversion of lanosterol to ergosterol. Although all the antifungals have some hepatotoxic potential, the imidazoles seem to have a higher incidence; therefore, it is important to determine liver status before prescribing. Of greater concern is the large list of interactions mostly related to cytochrome P450 metabolism, a very long list of prominent drugs, including the statins.

39. Inibizione degli enzimi coinvolti nella sintesi di ergosterolo da parte dei farmaci Antifunginei azolici, morfolinici e allilaminici.

40. Meccanismo di resistenza dei funghi agli azoli 1) Alterazione della 14 alfa demetilasi 2) Sovraespressione della lanosterolo demetilasi 3) Alterazione dei sistemi di efflusso 4) Cambiamento della composizione degli steroli di membrana della cellula funginea

42. FLUCITOSINA(5-fluorocitosina) cytosine deaminase Flucitosina 5 fluorouracile 5-fluorodeossiuridina monofosfato 5 fluorouracile Inibizionesintesi DNA Uracil fosforibosil trasferasi Acido 5 fluoro uridilico 5 fluorouracile Fosforilazione 5-fluoro-UTP Acido 5 fluoro uridilico Incorporato nella sintesi dell‘RNA con risultato di inibizione della sintesi proteica

43. ECHINOCANDINE The final milestone of antifungal drug discovery in the 20th century was the identification and development of echinocandin antifungal agents. Echinocandins are semisynthetic lipopeptides that inhibit synthesis of β-1,3-d-glucan in susceptible fungi, leading to damage of the fungal cell wall. Because a glucan-rich cell wall is a target not found in mammalian cells, these agents were predicted to be effective antifungal agents with very little collateral toxicity in mammalian cells—a prediction that has been proven true in clinical trials of patients with invasive candidiasis15-17 and aspergillosis. However, echinocandins still lack activity against some common opportunistic yeasts (Cryptococcus species) and less common molds (ie, Fusarium, Scedosporium, and Mucorales) that often develop as breakthrough infections in severely immunocompromised patients.

44. caspofungin, • micafungin • anidulafungin Echinocandine Inibizione della sintesi del glucano componente della membrana cellulare Micafungin was introduced into the market in 2005 Echinocandina B

46. Fks1p and Fks2p involvement in the synthesis of beta1:3 glucan in the cell walls.

47. Caspofungin Efficacy of Caspofungin in Invasive Aspergillosi (IA) Caspofungin (CPF) is the first approved member of the class of echinocandins and the only member currently licensed for the therapy of Invasive Aspergillosi. Echinocandins act as non-competitive inhibitors of the UDP-glucose- (1,3)-D -glucan- (3)- D -glucosyltransferase, commonly referred to as (1,3)-glucan synthase. This enzyme is especially important in the cell wall synthesis of yeasts and molds . CPF is active against pathogenic Aspergillus and Candida species.Like all echinocandins, CPF is a high-molecular-weight lipoprotein and can thus be administered by intravenous infusion only. Caspofungina Viene somministrata per via endovenosa

48. MECHANISM OF ACTION AND IN VITRO ACTIVITY In common with other echinocandins, micafungin inhibits the synthesis of 1,3-b-D-glucan, a major component of fungal cell wall, in a non-competitive, concentration-dependent manner. Micafungin has potent and fungicidal activity against a wide range of Candida spp. in vitro, including fluconazole-resistant Candida spp. and multidrug-resistant Candida spp. residing in biofilms . Micafungin has poor oral bioavailability and is only available for intravenous administration. The compound is extensively (>99%) bound to plasma proteins, metabolized by the liver, and excretion predominantly occurs via the fecal route.

49. Meccanismo di resistenza alle echinocandine Nel gene FKS1 è codificato l’enzima glucano sintasi mentre nel gene GNS1 è codificato un enzima che prende parte alla sintesi (estensione) degli acidi grassi. Mutazioni genetiche di laboratorio hanno messo in evidenza che la mutazione di questi enzimi porta alla comparsa di resistenza alle echinocandine

50. Eur J Med Res (2011) 16: 159-166