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

7. Microsporum canis (Tinea capitis)
Infezioni cutanee da funghi
Microsporum canis (Tinea capitis)
Trichophyton mentagrophytes

8. Tinea corporis
Tinea faciei
Tinea cruris

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

10. Oncimicosi

14. 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

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

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

17. 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

18. Topical allylamines Topical azoles Other topical antifungals
Generic Name
Brand Name
naftifine
Naftin
Topical azoles
Generic Name
Brand Name
clotrimazole
econazole
Spectazole
ketoconazole
Nizoral
oxiconazole
Oxistat
sertaconazole
Ertaczo
sulconazole
Exelderm
Other topical antifungals
Generic Name
Brand Name
butenafine
Mentax
ciclopirox
Loprox
clotrimazole-betamethasone
Lotrisone

19. Usi terapeutici : AMFOTERICINA B genera dei pori nella membrana
- 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

20. 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

21. 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 significant ly 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.

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

23. 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 umano particolarmente degli isoenzimi CYP2C9 e CYP3A4.

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

25. Fluconazole: Fluconazole is an oral and parenteral agent
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).

26. Voriconazole TRIAZOLI
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.

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

28. 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 membranadella cellula funginea

30. FLUCITOSINA (5-fluorocitosina)
cytosine deaminase
Flucitosina
5 fluorouracile
5-fluorodeossiuridina
monofosfato
5 fluorouracile
Inibizione sintesi 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

31. Echinocandine Caspofungina caspofungin, micafungin and anidulafungin
Inibizione della sintesi del glucano componente della membrana cellulare
Echinocandina B

32. Viene somministrata per via endovenosa
Caspofungina

33. 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.

34. 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

35. Chitin is made by chitin synthases requiring specific microvesicles, the chitosomes, for intracellular transport. Fungi contain several chitin synthases, some of which may be essential at a certain stage. This phenomenon is important to take into account for drug design. The most widely studied chitin synthase inhibitors are polyoxins and nikkomycins that probably bind to the catalytic site of chitin synthases.

36. La Chitina è un polimero della N-acetilglucosamina, costituente principale della membrana cellulare dei funghi
La Nikkomicina è un inibitore della sintesi della chitina

37. Sir,
Until the last decade, antifungal therapy was based mostly on drugs acting on the fungal membrane, such as amphotericin B and azoles, and the rationale for the use of combination therapy remained questionable.1 Thus, the only drug combination of two antifungals with two modes of activity used clinically, primarily in cryptococcosis, was amphotericin B and 5-fluorocytosine.2 The introduction of echinocandins, which act on the fungal cell wall by inhibiting glucan synthesis, opened the approach to explore different drug combinations, such as echinocandins and polyenes, or echinocandins and azoles,3,4 for various mycoses. Nikkomycin Z inhibits chitin synthesis, by acting as a competitive analogue of chitin synthase substrate UDP-N-acetylglucosamine.
3 Since chitin is found in most fungal cell walls, inhibition of its synthesis may be considered as a potentialmeans for antifungal therapy.

39. Voriconazole is a triazole antifungal agent and is a second generation synthetic derivative of fuconazole; it is effective against yeast and lamentous fungi. The primary mode of action of voriconazole is the inhibition of cytochrome P-450- mediated 14-α-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis and the resulting ergosterol depletion causes fungal cell wall destruction.

40. Severe phototoxicity associated with long-term voriconazole treatment.
J Dtsch Dermatol Ges. 2011 Apr;9(4): doi: /j x. Epub 2010 Nov 3.
Severe phototoxicity associated with long-term voriconazole treatment.
Vöhringer S, Schrum J, Ott H, Höger PH.
Department of Pediatric Dermatology, Catholic Children's Hospital Wilhelmstift, Hamburg, Germany.
Abstract
Voriconazole is a second-generation triazole antifungal approved for the treatment of invasive fungal infections, particularly with Aspergillus, Candida, Fusarium, and Scedosporium spp. Frequently reported adverse effects of voriconazole include visual disturbance (21 %), elevated liver enzymes (15.6 %) and rashes (7 %), which are largely attributable to drug-induced photosensitivity. We report a case of serious phototoxicity in a 8 year old boy who underwent chemotherapy for AML. He received voriconazole for the treatment and subsequent re-infection prophylaxis after pulmonary aspergillosis. One year after the start of therapy he developed blistering eruptions on his face after minimal sunlight exposure. Recent reports about the development of squamous cell carcinoma and melanoma, respectively, in children during and after oral therapy withvoriconazole seem to warrant systematic follow-up investigations of all voriconazole-treated patients.

41. Expert Rev Pharmacoecon Outcomes Res. 2010 Dec;10(6):623-36.
Pharmacoeconomics of voriconazole in the management of invasive fungal infections.
Al-Badriyeh D, Heng SC, Neoh CF, Slavin M, Stewart K, Kong DC.
College of Pharmacy, Qatar University, Doha, Qatar.
Abstract
The incidence of invasive fungal infection has risen in recent years with the introduction of more intensive chemotherapy regimens and the advent of stem cell and solid-organ transplants. In patients undergoing chemotherapy, mortality rates ranging from 50 to 90% have been associated with documented invasive fungal infection. Voriconazole is a second-generation triazole, which is a synthesized derivative of fluconazole. It was first approved for marketing in the USA in 2002.Voriconazole has excellent bioavailability and is available in oral and intravenous dosage form. It has extended-spectrum antifungal activity whereby it is highly effective against a variety of fungal organisms, including Candida, Fusarium, Paecilomyces and Scedosporium species, but it is especially known for its activity against the Aspergillu s species.Voriconazole has become widely used for three types of treatment strategies (i.e., targeted, empirical and prophylactic). However, voriconazole is a high-cost antifungal agent and, therefore, its effectiveness should be scrutinized, taking into consideration its cost in relation to the costs of other comparable antifungal agents. This article summarizes the 18 identified peer-reviewed publications on the pharmacoeconomics of voriconazole in the English literature, up to March 2010, and provides a view on its future role in therapy. Comparisons with existing antifungals are provided when possible to illustrate the potential role of voriconazole in a clinical setting. The studies took place in a variety of countries and were all retrospective in nature, with the majority suggesting that voriconazole is a more cost-effective option for antifungal treatment. Of the 18 evaluations, 11 were related to the economic impact of voriconazole against invasive aspergillosis only. Economic data to guide the use of voriconazole as prophylaxis or empirical therapy as well as targeted therapy against invasive candidiasis remain limited.

42. Major information on the best therapeutic strategies for
cryptococcal meningoencephalitis derives from therapeutic trials
involving HIV-positive [1,2,3] or HIV-negative patients [4].
According to the current Infectious Diseases Society of America
(IDSA) guidelines, the treatment should depend on anatomic site
and host’s immunological status. Induction therapy using a
combination of amphotericin B (AMB, 0.7–1 mg/kg/d) and
flucytosine (5FC, 100 mg/kg/d) for 2 weeks followed by a
consolidation phase of 10 weeks by fluconazole (FCZ, 400 mg/d)
should be prescribed for central nervous system infection (CNS) in
both HIV-positive and -negative patients, based mostly on data
extrapolated from trials in HIV-infected patients [5] and retrospective
studies onHIV-negative patients [6,7].
Conclusion: Our results support the conclusion that induction therapy with AMB+5FC for at least 14 days
should be prescribed rather than any other induction treatments in all patients with high fungal burden at baseline
regardless of their HIV serostatus and of the presence of proven meningoencephalitis.

43. Objectives: Invasive fungal infections are a major cause of mortality among patients at risk. Treatment
guidelines vary on optimal treatment strategies. We aimed to determine the effects of different antifungal
therapies on global response rates, mortality and safety.
Methods: We searched independently and in duplicate 10 electronic databases from inception to May
2009. We selected any randomized trial assessing established antifungal therapies for confirmed cases of
invasive candidiasis among predominantly adult populations. We performed a meta-analysis and then
conducted a Bayesian mixed treatment comparison to differentiate treatment effectiveness. Sensitivity
analyses included dosage forms of amphotericin B and fluconazole compared to other azoles.
Results: Our analysis included 11 studies enrolling a total of 965 patients. For our primary analysis of
global response rates, we pooled 7 trials comparing azoles to amphotericin B, Relative Risk [RR] 0.87 (95%
Confidence Interval [CI], 0.78–0.96, P = 0.007, I2 = 43%, P = We also pooled 2 trials of echinocandins
versus amphotericin B and found a pooled RR of 1.10 (95% CI, 0.99–1.23, P = 0.08). One study compared
anidulafungin to fluconazole and yielded a RR of 1.26 (95% CI, 1.06–1.51) in favor of anidulafungin. We
pooled 7 trials assessing azoles versus amphotericin B for all-cause mortality, resulting in a pooled RR of
0.88 (95% CI, 0.74–1.05, P = 0.17, I2 = 0%, P = 0.96). Echinocandins versus amphotericin B (2 trials) for all cause
mortality resulted in a pooled RR of 1.01 (95% CI, 0.84–1.20, P = 0.93). Anidulafungin versus
fluconazole resulted in a RR of 0.73 (95% CI, 0.48–1.10, P = 0.34). Our mixed treatment comparison
analysis found similar within-class effects across all interventions. Adverse event profiles differed, with
amphotericin B exhibiting larger adverse event effects.
Conclusion: Treatment options appear to offer preferential effects on response rates and mortality.
When mycologic data are available, therapy should be tailored.

44. Invasive candidiasis has emerged as an important nosocomial infection, especially in critically ill patients.
We review the epidemiology of invasive candidiasis with an emphasis on data from Taiwan. An increasing incidence of candidemia became apparent from 1980 to the end of the 1990s, followed by relative stability.
Crude mortality rates of patients with candidemia were in the range of 35% to 60%. Candida albicans remains the predominant cause of invasive candidiasis in Taiwan and accounts for more than 50% of all cases. Candida tropicalis, Candida glabrata and Candida parapsilosis are the three most common nonalbicans Candida species that cause invasive candidiasis. The above four Candida species account for more than 90% of invasive candidiasis in Taiwan. Overall, invasive Candida isolates have remained highly susceptible to fluconazole (> 90% susceptibility) over the past two decades. However, periodic surveillance is needed to monitor antifungal resistance because reduced fluconazole susceptibility in non-albicans
Candida is not an uncommon trend. Voriconazole and echinocandins continue to exhibit excellent in vitro activity against invasive Candida isolates. [J Formos Med Assoc 2009;108(6):443–451]

46. Topical polyene or azole antifungal agents are effective in most cases
Topical polyene or azole antifungal agents are effective in most cases. Drug choice is dictated by several factors, including the patient’s medical history, oral symptoms and predicted compliance with application method. Some common regimes are given below.
Nystatin oral suspension ( units ⁄mL – 1 mL topically), or nystatin pastilles ( IU) four times daily for 7 to 14 days should resolve most local candidal infections. Note that some studies indicate nystatin to be ineffective for Candidal lesions in cancer patients.

47. http://infection.thelancet.com Vol 6 April 2006