Farmaci antifunginei

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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 luomo
1 Dermatophytes Microsporum, Epidermophyton e
Trichophyton 2 Candida 3 Aspergillus 4
Cryptococcus 5 Rhizopus ...
Microsporum canis
Candida albicans
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Infezioni cutanee da funghi
Microsporum canis (Tinea capitis)
Trichophyton mentagrophytes
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Tinea corporis
Tinea faciei
Tinea cruris
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Candidiosi, Stomatite, Mughetto
Intertrigine da candida (ascelle)
Candidiosi da pannolino
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Oncimicosi
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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

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Farmaci antifunginei suddivisi per classi
ECHINOCANDINE Caspofungin, anidulafungin,
micafungin PEPTIDE-NUCLEOSIDE Nikkomicina
Z DERIVATI TETRAIDROFURANICI Sordarine,
azasordarine ALTRI Griseofulvina
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Nature Reviews Drug Discovery AOP, published
online 20 August 2010 doi10.1038/nrd3074
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MECCANISMO DI AZIONE
7 Inibitori della sintesi proteica Sordarine,
azasordarine
1 Agenti che interferiscono con l
integritadella 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
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Topical allylamines
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
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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 dell80
in sogggetti con AIDS.) - Meningite criptococcica
in pazienti con HIV - Criptococcosi polmonare -
Infezioni funginee del SNC
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Effetti collaterali Amfotericina B
Effetti collaterali generali Perdita di peso
corporeo Diarrea, indigestione, perdita
dellappetito, nausea, vomito Febbre, mal di
testa Effetti collaterali gravi Aritmia
cardiaca, ipotensione tromboflebiti Ipocaliemia An
afilassi Nefrotossicità convulsioni
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In addition to infusion-related adverse
effects, Amphotericin B ( AmB) may be associated
with considerable cumulative toxicity like
cardiotoxicity, neurotoxicity and, most
notably, nephrotoxicity (6080 of patients), the
latter manifesting in tubular injury and a poorly
understood renal vasoconstriction. Although AmBs
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.
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Ketoconazolo
Lo Squalene è il precursore di tutte le famiglie
di steroidi
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Meccanismo di azione
Il ketoconazolo può essere micostatico o
fungicida a seconda delle dosi. Inibisce la
sintesi dellergosterolo 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.
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Classification of triazoles First generation of
triazoles Fluconazole Itraconazole Second
generation of triazoles Voriconazole
Posaconazole Ravuconazole
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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).
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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.
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Inibizione degli enzimi coinvolti nella sintesi
di ergosterolo da parte dei farmaci Antifunginei
azolici, morfolinici e allilaminici.
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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
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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 dellRNA con risultato
di inibizione della sintesi proteica
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caspofungin, micafungin and anidulafungin
Echinocandine Caspofungina
Inibizione della sintesi del glucano componente
della membrana cellulare
Echinocandina B
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Viene somministrata per via endovenosa
Caspofungina
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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 (gt99) bound to plasma proteins,
metabolized by the liver, and excretion
predominantly occurs via the fecal route.
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Meccanismo di resistenza alle echinocandine
Nel gene FKS1 è codificato lenzima 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
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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.
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La Chitina è un polimero della N-acetilglucosamina
, costituente principale della membrana cellulare
dei funghi
La Nikkomicina è un inibitore della sintesi della
chitina
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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.
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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-a-lanosterol demethylation, an
essential step in fungal ergosterol biosynthesis
and the resulting ergosterol depletion causes
fungal cell wall destruction.
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J Dtsch Dermatol Ges. 2011 Apr9(4)274-6. doi
10.1111/j.1610-0387.2010.07563.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 see
m to warrant systematic follow-up investigations
of all voriconazole-treated patients.
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Expert Rev Pharmacoecon Outcomes Res. 2010
Dec10(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.
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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
hosts immunological status. Induction therapy
using a combination of amphotericin B (AMB, 0.71
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 AMB5FC 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.
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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, 0.780.96, P
0.007, I2 43, P 0.09. We also pooled 2
trials of echinocandins versus amphotericin B and
found a pooled RR of 1.10 (95 CI, 0.991.23, P
0.08). One study compared anidulafungin to
fluconazole and yielded a RR of 1.26 (95 CI,
1.061.51) 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, 0.741.05, 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, 0.841.20, P 0.93).
Anidulafungin versus fluconazole resulted in a RR
of 0.73 (95 CI, 0.481.10, 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.
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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 (gt 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
2009108(6)443451
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Topical polyene or azole antifungal agents are
effective in most cases. Drug choice is dictated
by several factors, including the patients
medical history, oral symptoms and predicted
compliance with application method. Some common
regimes are given below. Nystatin oral suspension
(100 000 units /mL 1 mL topically), or nystatin
pastilles (100 000 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.
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