ANTIFUNGAL

dr. Dewi Anggraini, SpMK

 KLASIFIKASI
• Azol
• Amphotericine B
• Echinocandin
 AZOL
• Azole antifungal agents • The azoles that are
have added greatly to the
therapeutic options for
treatment of systemic
fungal infections.
available for systemic use
can be classified into two
groups:
– the triazoles:
• Fluconazole
• Itraconazole
• Voriconazole
• Posaconazole
• Isavuconazole)
– the imidazoles:
• ketoconazole
 AZOL
• Members of the triazole family are some of the
most widely used antifungal agents.
• The drugs in this class offer activity against many
fungal pathogens without the serious nephrotoxic
effects observed with amphotericin B.
• Newer azole agents have emerged as first-line
therapies for several severe fungal diseases, such
as invasive aspergillosis, for which voriconazole
has become the standard of care.
 MECHANISM OF ACTION
• The azole antifungals work primarily by inhibiting
the cytochrome P450-dependent enzyme
lanosterol 14-alpha-demethylase
• This enzyme is necessary for the conversion of
lanosterol to ergosterol, a vital component of the
cellular membrane of fungi.
• Disruptions in the biosynthesis of ergosterol
cause significant damage to the cell membrane
by increasing its permeability, resulting in cell
lysis and death.
AZOL
AZOL
AZOL
AZOL
AZOL
 AZOL
• Agents within the azole class vary importantly with regards to
spectrum of activity, pharmacokinetic profiles, and toxicities.
• For example, fluconazole has excellent activity against yeasts but
offers no protection against molds.
• An extended spectrum is provided by itraconazole, but inconsistent
bioavailability limits use of this agent in severely ill patients.
• Voriconazole is the first-line agent for the treatment of invasive
aspergillosis, but its bioavailability is unpredictable and genetically
determined, it is associated with unique side effects, and it lacks
activity against the Mucorales, the agents of mucormycosis.
• Among the azoles, posaconazole and isavuconazole have the
broadest spectrum of activity. Both are available as intravenous and
oral formulations.
 MICROBIOLOGIC ACTIVITY
• Each member of the azole class exhibits a
unique spectrum of activity, although
fluconazole, itraconazole, voriconazole,
posaconazole, and isavuconazole all
demonstrate similar activity against most
Candida species
• Fluconazole :
– has activity limited to yeasts and some
clinical activity against the endemic fungi
(Histoplasma, Blastomyces, Coccidioides,
and Paracoccidioides spp), although it is
not as potent as itraconazole for the
endemic fungi.
– In general, it has excellent activity against
Candida species but has less activity
against C. glabrata and no activity against
C. krusei. It has excellent activity against
Cryptococcus species.
• Itraconazole :
– offers a broader spectrum of activity than
fluconazole, including endemic fungi,
Sporothrix schenckii, and Aspergillus species.
It is also active against the dematiaceous
(brown-black) molds.
• Voriconazole :
– has enhanced activity against Aspergillus
species and other hyalohyphomycoses,
including Scedosporium apiospermum and
Fusarium species. It also has activity against
dematiaceous molds. Voriconazole
demonstrates superior activity in vitro against
fluconazole-resistant C. glabrata and against
C. krusei.
• The introduction of posaconazole and
isavuconazole has expanded the spectrum of
the azole agents further to include the
Mucorales while maintaining activity against
yeasts and molds
• Ketoconazole is active against the endemic
mycoses, dermatophytes, and Candida spp.
 AMPHOTERICIN B
• Amphotericin B is a polyene antifungal agent with activity
in vitro against a wide variety of fungal pathogens
• Despite the introduction of newer antifungal agents for the
treatment of systemic mycoses, amphotericin B remains the
standard treatment for many severe, invasive fungal
infections.
• However, because of toxicities associated with its
intravenous use, along with the expanded availability of
safer treatment options, it is frequently reserved for
patients who have severe, life-threatening invasive fungal
infections or who are unable to tolerate alternative
antifungal agents.
 MECHANISM OF ACTION
• Amphotericin B exerts its antifungal effect by
disruption of fungal cell wall synthesis because
of its ability to bind to sterols, primarily
ergosterol, which leads to the formation of
pores that allow leakage of cellular
components.
• This affinity may also account for its toxic
effects against select mammalian cells.
AMPHOTERICIN B
AMPHOTERICIN B
AMPHOTERICIN B
AMPHOTERICIN B
AMPHOTERICIN B
 LIPID-BASED AMPHOTERICIN B
FORMULATIONS
• Lipid-based formulations of amphotericin B
have been introduced in an attempt to reduce
the toxicities associated with amphotericin B
deoxycholate
LIPID-BASED AMPHOTERICIN B
FORMULATIONS
 SPECTRUM OF ACTIVITY
• Activity of amphotericin B has been demonstrated in
vitro against a wide variety of clinical fungal isolates,
including most Candida spp, Aspergillus spp, the
Mucorales, all of the endemic mycoses, and most
hyaline and brown-black molds. Activity has also been
demonstrated against Leishmania spp.
• Organisms that are usually resistant to amphotericin B
include the organisms that cause
chromoblastomycosis, Aspergillus terreus, Candida
lusitaniae, Scedosporium spp, and some Fusarium spp
 ECHINOCANDIN
• development of echinocandins, was a
milestone achievement in antifungal
chemotherapy.
• Three semi-synthetic echinocandin derivatives
have been developed for clinical use:
– caspofungin
– micafungin
– anidulafungin
 ECHINOCANDIN
• Like other large lipopeptide antibiotics, these
drugs have limited oral bioavailability and
must be administered by intravenous infusion.
• Experience with this antifungal class suggests
that it is among the best tolerated and safest
class of antifungals available.
 MECHANISM OF ACTION
• The mechanism of action of the echinocandins exploits a
biochemical pathway unique to fungi, which is different
from the mechanisms of other antifungal drugs.
• Echinocandins target fungal cell glucan synthesis by
competitively inhibiting the beta-1,3-D-glucan synthase
enzyme complex in susceptible fungi
• Beta-glucans and the intracellular beta-glucan synthase
complex blocked by echinocandins are not present in
human cells.
• In addition, the mechanism of action of the echinocandins
appears to complement the antifungal effects of the other
antifungal drug classes, offering the potential for
combination therapy.
ECHINOCANDIN
ECHINOCANDIN
ECHINOCANDIN
ECHINOCANDIN
ECHINOCANDIN
ECHINOCANDIN
 OVERVIEW OF CLINICAL USES
• Echinocandins are widely used for the treatment
of invasive candidiasis, especially in critically ill
and neutropenic patients
• They are also used for empiric antifungal therapy
in patients with neutropenic fever.
• They are sometimes used in combination with
voriconazole for the initial treatment of invasive
aspergillosis or as part of a combination
antifungal regimen with voriconazole or a lipid
formulation of amphotericin B for salvage therapy
of invasive aspergillosis
 OVERVIEW OF CLINICAL USES
• The major advantages of echinocandins
relative to other antifungal agents are their
fungicidal activity against Candida spp,
including fluconazole-resistant C. glabrata and
C. krusei, combined with their relatively low
potential for renal or hepatic toxicity or
serious drug-drug interactions.
 OVERVIEW OF CLINICAL USES
• All three echinocandins have been approved by the US
Food and Drug Administration (FDA) for the treatment of
esophageal candidiasis and invasive candidiasis in adults,
and caspofungin has been approved for these indications in
children over three months of age
• Caspofungin has also been FDA approved as an empiric
antifungal agent for febrile neutropenia and for salvage
therapy of invasive aspergillosis in patients who have failed
or are intolerant of other antifungal agents in adults and
children over three months of age.
• Micafungin has also been FDA approved as a prophylactic
agent for the prevention of Candida infections in adults
undergoing hematopoietic cell transplantation.
 ANTIFUNGAL RESISTANCE
• The use of antifungal drugs in the therapy of fungal diseases can
lead to the development of antifungal resistance.
• Resistance has been described for virtually all antifungal agents in
diverse pathogens, including Candida and Aspergillus species.
• Drug resistance genes and genome mutations have been identified.
• Therapeutic choices are limited for the control of fungal diseases,
and it is tempting to combine several drugs to achieve better
therapeutic efficacy.
• In the recent years, several novel resistance patterns have been
observed, including antifungal resistance originating from
environmental sources in Aspergillus fumigatus and the emergence
of simultaneous resistance to different antifungal classes (multidrug
resistance) in different Candida species.
 ANTIFUNGAL RESISTANCE
• The three basic resistance mechanisms to antifungal
drugs.
1. decrease of effective drug concentration with specific
mechanisms including increased drug efflux, increased
number of targets, drug sequestration of extracellular
and intracellular origins, and poor pro-drug conversion
2. drug target alterations
3. metabolic bypasses.
• Genome mutations are generally responsible for these
three basic principles.
• Drug sequestration can be mediated by the formation
of matrix polymers in biofilms