Antifungal Agents

ANTIFUNGAL
AGENTS
ANTIFUNGAL AGENTS
Antifungal agents
Increase of human fungal infections
mainly due to advances in surgery,
cancer treatment, critical care, increase
in the use of broad spectrum antibiotics
and HIV
Increased number of patients at risk
Antifungals available : systemic drugs,
oral drugs for mucocutaneous infections
and topical drugs
Evolution of antifungal
agents
POLYENE ANTIFUNGALS
AMPHOTERICIN B
NYSTATIN
Fungicidal against both filamentous and
yeastlike fungi, Histoplasma, Blastomyces,
Coccidioides, Cryptococcus, Cnadida,
Aspergillus and Sporotrichum
In vitro activity against some protozoa
Generally acts on sterols in the cytoplasmic
membrane of fungi leading to rapid leakage
and fungal death
AMPHOTERICIN B: CHEMISTRY
Produced by Streptomyces nodosus
Polyene macrolide
Water insoluble, prepared as a
colloidal suspension or in a lipid
associated delivery system
AMPHOTERICIN B: PHARMACOKINETICS
Poor GI absorption
Oral administration is effective for fungal
infections on the lumen of the GI tract
>90% protein bound
Serum t1/2 15 days
Large Vd but CSF concentrations is only 2-3%
of plasma concentrations
Poor CSF penetration, may require intrathecal
administration in cases of meningitis
Fugicidal and fungistatic
AMPHOTERICIN B: MECHANISM OF ACTION

Binds to Ergosterol and alters cell permeability
Forms pores in the cell which allows leakage of
intracellular ions and macromolecules
Binds to human membrane sterols, accounting
for toxicity
Resistance if ergosterol binding is impaired
either by increasing ergosterol concentration
or modifying the sterol of the target molecule
AMPHOTERICIN B: LIPID
FORMULATIONS
Therapy is limited by toxicity
Lipid binding of the drug causes less
binding to mammalian membranes
permitting the use of effective doses
of the drug.
Lipid vehicle serves as a reservoir
AMPHOTERICIN B: ADR
Infusion related toxicity: fever, chills, muscle spasms,
vomiting, headache , hypotension
Ameliorated by slow IV infusion or decreasing the dose
Premedications with antihistamines
Start with a test dose
Slower toxicity:
Azotemia is variable but can be serious enough to
necessitate dialysis
Renal toxicity commonly presents with RTA ( renal
tubular acidosis with severe K and MG wasting)
Attenuated by preloading with saline
After intrathecal administration: seizures, chemical
arachoidits
AMPHOTERICIN B: Antifungal activity

BROADEST SPECTRUM OF ACTIVITY
Candida albicans
Cryptococcus neoformans
Histoplasma capsulatum
Blastomyces dermatidis
Coccidioides imimtis
Aspergillus fumigatus
Candida lusitaniae and Pseudallescheria
boydii are resistant
AMPHOTERICIN B: Clinical Use

Drug of choice for nearly all life
threathening mycotic infections
Initial induction therapy for serious fungal
infections and is concomitantly replaced
by azoles
Fungal pneumonia, cryptococcal
meningitis, sepsis, systemic fungal disease
Local application: Fungal keratitis, fungal
arthritis, bladder irrigation in Candiduria
NYSTATIN
More soluble than Amphotericin B
Used primarily as a topical
preparation
Active against most Candida species
Not absorbed from skin or GI tract
No parenteral administration due to
toxicity
AZOLES
Synthetic compounds
Imidazoles: Ketoconazole, Miconazole,
Clotrimazole
Triazoles: Itraconazole, Fluconazole,
Vorioconazole
AZOLES: Mechanism of Action

Reduction of ergosterol synthesis by
ionhibition of fungal cytochrome P450
enzymes
AZOLES: Clinical use

Candida species
Cryptococus neoformasns
B;astomyces
Coccidiomycosis
Histoplasmosis
Dermatophytes
Aspergillus for Itraconazole and Voriconazole
Pseudallscheria boydii
AZOLES: ADRs
Relatively non toxic
Minor GI upset
Abnormalities in liver enzymes
Ketoconazole
Systemic use discontinued because
of its great propensity to inhibit
mammalian cytochrome P450
enzymes
Used in dermatologic infections
Itraconazole
Available in oral and IV formulations
Drug absorption is increased by food or low
gastric pH
Reduced bioavailability when taken with
Rifampicin, Rifabutin, Rifapentine
Poor CSF penetration
Drug of choice for HIstoplasma, Blastomyces
and Sporotrix infections
Used extensively in the treatment of
dematophytoses and onychomycosis
Fluconazole
Highly water soluble and high CSF penetration
High oral bioavailability
Better GI tolerance, fewer hepatic enzyme
interactions: widest therapeutic index
Azole of choice in the treatment and
secondary prophylaxis of Cryptococcal
infections
Equivalent to Amphotericin B in the treatment
of Candidemia
Reduce fungal disease in bone marrow
transplant and AIDS patients
Voriconazole
Good oral bioavailability
Low propensity for mammalian
cytochrome P 450 inhibition
Causes Blurring of vision and altered
color perceptions
Excellent activity against Candida,
effective in the treatment of invasive
Aspergillosis
MICONAZOLE/ CLOTRIMAZOLE
Topically active
Fungicidal when administered
topically
Poor CSF penetration
Used in ringworm infections and
vulvovaginal candidiasis
FLUCYTOSINE
Water soluble pyrimidine analog related
to 5 FU
09% absorbed with peak serum
concentrations 1-2 hours after oral
administration
Poor protein binding, penetrates well into
all body fluid compartments including
CSF
Eliminated by glomerular filtration, levels
rise rapidly in renally impaired patients
FLUCYTOSINE: Mechanism of Action

Taken up by fungal cells via cytosine
permease
Converted to 5FU and the to 5
fluorodeoxyuridine 5 F-dUMP and
fluorouidine 3 PO4
Inhiobits DNA and RNA synthesis
Resistance seen in monotherapy
Acts synergystically with Amphotericin B.
FLUCYTOSINE: ADRs
Toxicity related to the formation of 5
FU
Anemia, leukopenia,
thrombocytopoenia
Narrow therapeutic window
Used in Cryptococcal infections
Griseofulvin
Used in the systemic treatment of
dermatophytosis, Epidermophyton,
Microsporum, Trichophyton,
Binds to keratin and is deposited in
newly forming skin
Terbinafine
Used in the treatment of
dermatophytosis, specifically
onychiomycosis
Like Griseofulvin, it is Keratophyllic
Does not seem to affect cytochrome
P450 enzymes
Echinocandins/
Capsofungin
Newest class of antifungals
Cyclic peptides linked to a long chain
fatty acid
Acts at the level of the fungal wall by
inhibiting the synthesis of beta 1-3
glucan, resulting in cell wall disruption
Used in Invasive Aspergillosis who have
failed to respond to Amphotericin B.
To determine the susceptibility of fungi to

antifungal agents
Concentration that inhibits the growth of

fungi = Minimum inhibitory concentration
(expressed as g/ml)
Several methods can be used to define the
MIC
MIC reading = depends on the method
used
(EUCAST, CLSI, E-test,)
MICs defined via E-test
Growth of fungus
MIC= zone of inhibition
MICs help, but hard to standardize

Correlations appear possible based on individual
isolates. Broad correlations based on multiple
isolates are still lacking
Understanding this helps a lot when trying to
correlate outcome with MIC
- Some patients get better despite MICs
- Some patients just dont get better despite
MICs
No rule when it correlates/not correlates
AZOLE RESISTANT ASPERGILLUS

FUMIGATUS
Antifungal susceptibility testing
Based on NCCLS M27-A

document
Macrodilution
Microdilution
Disk diffusion
Agar
dilution
E
test
Variables: inoculum, medium, PH, incubation & temperature,
MIC
Azole cross-resistance
Mechanisms of resistance to drug
action
Modification of the drug itself
Modification in quantity or quality of the
drug target
Reduced access to the target
The resistance may result from a

combination of these mechanisms
Factors in resistance
Modifications of the azoles have not yet
been documented as a factor
Differing binding affinities of azoles
Some species of Candida
Efflux of fluconazole
development of fluconazole resistance in
some Candida species
achieved by increased expression of the
multidrug resistance transporter proteins
(especially MDR1)
Factors in resistance
Overexpression of 14--demethylase
an azole-resistant strain of C glabrata
the mechanism of cross-resistance exhibited
with itraconazole and fluconazole
Altered membrane sterol composition

methylated sterols, such as methylfecosterol
replacing ergosterol
an azole-resistant and polyene-resistant C
albicans mutant

Antifungal Agents

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ANTIFUNGAL

AMPHOTERICIN B: MECHANISM OF ACTION

AMPHOTERICIN B: Antifungal activity

AMPHOTERICIN B: Clinical Use

AZOLES: Mechanism of Action

AZOLES: Clinical use

FLUCYTOSINE: Mechanism of Action

To determine the susceptibility of fungi to

Concentration that inhibits the growth of

MICs defined via E-test

MIC= zone of inhibition

MICs help, but hard to standardize

AZOLE RESISTANT ASPERGILLUS

Antifungal susceptibility testing

Based on NCCLS M27-A

The resistance may result from a

Altered membrane sterol composition

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