increasing

The incidence of fungal infections is

changing
The spectrum of fungal disease is

Selection of fungi is a reality

Resistance of fungi is on the rise
recognized
Cross resistance is increasingly
•Better diagnosis
• More broadspectrum antibiotics
• Higher age of patient population
• More complex interventions

(e.g.transplants)
• More intensive cytotoxic therapy
• More immunosuppressive therapy
• Less mortality from other causes
• More high risk patients
 Specificity (no side effects).
 Activity throughout the body.
 Broad spectrum.
 Kill microbes, not just prevent growth.
 No drug-drug interactions.
 Low cost.
 Antifungals work by exploiting differences
between mammalian and fungal cells to kill the
fungal organism without dangerous effects on the
host.
 Unlike bacteria, both fungi and humans are

eukaryotes.
 Thus fungal and human cells are similar at the

molecular level.
 This makes it more difficult to find or design
drugs that target fungi without affecting human
cells.
 Consequently, many antifungal drugs cause side-

effects.
 Some of these side-effects can be life-threatening if

the drugs are not used properly.

 Apart from side-effects like liver-damage or
affecting estrogen levels , many medicines can
cause allergic reactions in people.
 For example, the azole group of drugs is known to

have caused anaphylaxis.

 Prophylaxis
 Empirical use
 Preemptive use
 Treatment
Empirical :
 based on observation or experiment , not on theory
 regarding sense-data as valid information
e.g. “an empiric = a quack doctor“
Pre-emptive :
to go on the offensive in order to avert an enemy
attack
 Cell membrane
Fungi use principally ergosterol
instead of cholesterol

DNA Synthesis
Some compounds may be
selectively activated by fungi,
arresting DNA synthesis.

Cell Wall
Unlike mammalian cells, fungi
have a cell wall

Atlas of fungal Infections, Richard Diamond Ed. 1999

Introduction to Medical Mycology. Merck and Co. 2001
Cell membrane
• Polyene antibiotics
• Azole antifungals

DNA/RNA synthesis
• Pyrimidine analogues
- Flucytosine

Cell wall
• Echinocandins
-Caspofungin acetate
(Cancidas)
 Different classes of drugs target the
plasma membrane, sterol biosynthesis,
DNA biosynthesis, and β-glucan
biosynthesis
 Fungal membranes and sterol biosynthetic
enzymes are different enough from ours
that these agents can kill fungi but not us
 Fungi make β-glucan, we don’t, so drugs
that target β-glucan biosynthesis have low
side-effects
 Membrane disrupting agents
Amphotericin B, nystatin
 Ergosterol synthesis inhibitors

Azoles, allylamines, morpholine

 Nucleic acid inhibitor

Flucytosine
 Anti-mitotic (spindle disruption)

Griseofulvin
 Glucan synthesis
inhibitors
Echinocandins

 Chitin synthesis
inhibitor
Nikkomycin

 Protein synthesis inhibitors

Sordarins, azasordarins
Cell membrane
• Polyene antibiotics
- Amphotericin B, lipid
formulations
- Nystatin (topical)

• Azole antifungals
- Ketoconazole
- Itraconazole
- Fluconazole
- Voriconazole
- Miconazole, clotrimazole (and
other topicals)
 Thesepolyene antimycotics are typically
obtained from some species of Streptomyces
bacteria.
 The polyenes bind to ergosterol in the
fungal cell membranewhich is the main
component of fungal cell membranes,
forming a transmembrane channel that
leads to monovalent ion (K+, Na+, H+, Cl-)
leakage which is the primary effect leading
to fungal cell death.
 The actual mechanism of action may be
more complex and multi-faceted.
 Amphotericin B, nystatin and natamycin

are examples of polyene antimycotics.

 Resistance may develop from altered sterols or
decreased sterols. It is cidal.
 Mammalian and fungal membranes both contain
sterols, a primary membrane target for
amphotericin B.
 Because mammalian and fungal membranes are

similar in structure and composition, this is one

mechanism by which amphotericin B causes
cellular toxicity.
 Amphotericin B molecules can form pores in the

host membrane as well as the fungal membrane.

 This impairment in membrane barrier function
can have lethal effects.
 Amphotericin administration is limited by

infusion-related toxicity.
 This is thought to result from innate immune

production of proinflammatory cytokines.

 ergosterol

ergosterol with
pore

+ a polyene
 most systemic fungi

 i.v., topical and oral preparations for oral

thrush (t½ - 24 hours)
 mostly metabolized
 some is excreted by kidney
 does not readily pass the blood-brain barrier
 hypersensitivity-anaphylaxis- hematologic
 fever, chills, headache, nausea
 thrombophlebitis
 hemolytic anemia
 renal toxicity (severity reduced with
sodium loading)
 hepatic damage
 hypokalemia
Deep-seated fungal infections
1) Liposomal amphotericin B
2) Amphotericin B colloidal dispersion
3) Amphotericin B lipid complex
 the incorporation of amphotericin B into a

lipid-based carrier system, which alters the

pharmacokinetics and tissue distribution of
the drug.
 similar to amphotericin B
 used topically and for GI use
 used against candida and dermatophytes
(Epidermophyton, Trichophyton, Microsporum).
 Azoleantifungal drugs inhibit the enzyme
lanosterol 14 α-demethylase; the enzyme
necessary to convert lanosterol to
ergosterol.
 Depletion of ergosterol in fungal
membrane disrupts the structure and many
functions of fungal membrane leading to
inhibition of fungal growth
Imidazoles
 Miconazole –Micatin
 Ketoconazole
 Clotrimazole (Canesten)
 Econazole

Triazoles
 Fluconazole
 Itraconazole
 Posaconazole
 Voriconazole
 The triazoles are newer, less toxic and more
effective

Thiazoles
 Abafungin
 Spectrum: yeasts and moulds - poor
absorption limits its role for severe
infections, generally used in mucosal
infections only
  Good activity against C. albicans and
Cryptococcus neoformans
 Non-albicans Candida species more likely

to exhibit primary resistance

Always resistant Sometimes resistant

C. krusei > C. glabrata > C. parapsilosis

C. tropicalis
C. kefyr
 Allylamines inhibit, squalene epoxidase
another enzyme required for ergosterol
synthesis:
 Terbinafine –"Lamisil"
 Amorolfine
 Naftifine –"Naftin"
 Echinocandins inhibit the synthesis of glucan
in the cell wall, probably via the enzyme 1,3-
β glucan synthase
 Anidulafungin
 Caspofungin
 Micafungin

Active against Aspergillus species

Activity against other yeast and moulds is less

well described or variable
Flucytosine is an antimetabolite.
Monotherapy : now limited

}
 Candidiasis In combination with
 Cryptococcosis amphotericin B or
 ?Aspergillosis
fluconazole.
Griseofulvin binds to polymerized
microtubules and inhibits fungal mitosis;
 It is derived from the mold Penicillium
griseofulvum
 It binds to keratin in keratin precursor cells
and makes them resistant to fungal
infections.
 It is only when hair or skin is replaced by the

keratin-griseofulvin complex that the drug

reaches its site of action.
 Griseofulvin will then enter the dermatophyte

through energy dependent transport

processes and bind to fungal microtubules..
 This alters the processing for mitosis and
also underlying information for deposition of
fungal cell walls.
 Griseofulvin is used to treat the following

fungal infections:
Tinea capitis
Tinea pedis
Tinea unguium (onychomycosis)
Tinea cruris
Tinea barbae
 Can reduce the effectiveness of oral
contraceptives as it a cytochrome p450
enzyme inducer
 Confusion
 Considered unsafe for those with Porphyria
 Diarrhea
 Dizziness
 Fatigue
 Headache
 Intrinsic resistance
 Replacement with a more resistant species
 Replacement with a more resistant strain
 Transient gene expressions that cause temporary
resistance (epigenetic resistance)
 Alterations in cell type
 Genomic instability within a single strain
(population bottleneck)
 HOST

Immune status
Site of infection
Severity of infection
Foreign devices
Noncompliance with drug regimen
 FUNGUS

Initial MIC
Cell type: Yeast/hyphae..
Genomic stability
Biofilm production
Population bottlenecks
 DRUG

Fungistatic nature
Dosing
Pharmacokinetics
Drug-drug interactions
 Proper dosing strategies

 Restricted and well-defined indications for

prophylaxis with azoles

 Fungi will continue to develop NEW

resistance mechanisms!..
 Antifungal resistance is a complex, gradual and
multifactorial issue

 Several uncertainties remain

 Molecular assays to detect resistance are not

simple

 The best way to improve the efficacy of

antifungal therapy is to improve the immune status
of the host