أستاذنا الدكتور سمير الأنصاري

1. Antifungal Agents
SAMIR EL ANSARY

3. Wide-spectrum
antibiotics surgery
Immunosuppressant
agents &
chemotherapy
AIDS
Increase
risk

4. Fungal infections = mycoses
• Opportunistic or primary
• Systemic or local
• Slow onset
• Long duration of therapy
• Difficult to diagnose & eradicate
• Symptoms vary from cosmetic to life
threatening

5. Antifungal drugs
• Work by exploiting differences between
mammalian and fungal cells to kill the fungal
organism without dangerous effects on the
host.
• Both fungi and humans are eukaryots.
• Difficult to find or design drugs that target fungi
without affecting human cells. (side effects)

6. Fungal cell membranes have a
unique sterol, ergosterol, which
replaces cholesterol found in
mammalian cell membranes

8. Antifungal drugs
Systemic & topical
Some are fungistatic,
while others are fungicidal

9. • Amphotericin B.
• Azoles
• Flucytosine
• Echinocandins
systemic
/systemic
• Griseofulvin
• Terbinafine
Systemic
/mucocutaneous
• Nystatine
• Topical Azoles
• Topical Allylamines
Topical
/mucocutaneous

10. Systemic antifungal drugs for
systemic infections

11. AMPHOTERICIN B
• Broad-spectrum polyene macrolide
antibiotic is the most potent antifungal
agent for systemic mycosis, in clinical use
since 1960
• Fungicidal drug at higher concentrations
& static at lower levels.

12. AMPHOTERICIN B
Produced by Streptomyses nodosum
• CSF conc.= 2-3 % of blood conc.
• Highest concentrations in liver, spleen,
bone marrow with less in kidneys and
lungs.

13. Mechanism of Action

14. MECHANISM OF ACTION
• High affinity for fungal ergosterol, forms
“micropore” in fungal cell membrane
through which ions, amino acids, & other
water soluble substances move out.

15. MECHANISM OF ACTION
• Markedly increases cell permeability.
• Cholestrol, present in host cell
membranes, closely resembles fungal
ergosterol & thus explains the high
toxicity of AMB in humans

17. Clinical use
• Treatment of nearly all life threatening mycotic
infections.
• For systemic disease: slow IV
o Local:
o Keratitis& corneal ulcers: drops, conjunctival irrigation,
o Candiduria: bladder irrigation
o Fungal arthritis: local injection

18. Side effects
• Infusion related
Fever & chills,
Dyspnea,
Nausea &vomiting,
Hypotension,
Convulsions
• Cumulative toxicity
Nephrotoxicity
K & Mg wasting
Anemia
(↓erythropoietin)
• To reduce the severity of the infusion-related reactions,
pretreatment with an antipyretic (acetaminophen),
antihistamines, and antiemetics may be given.

19. Liposomal Amphotericin B
• New lipid formulations
• Amphotericin B is incorporated into lipid
formulations to reduce toxicity &
enhance efficacy.
• This allows higher dose to be used
without increasing the toxicity.
• Much more expensive than ordinary
AMB.

20. KEY POINTS
• AMB is not absorbed enterally; hence can be given
orally for intestinal candidiasis.
• Drug concentration achieved in infected skin is
very low, & hence ineffective against superficial
fungal infections.
• Penetration in brain & CSF is poor (but extremely
effective in fungal meningitis when combined with
5-FC)

21. FLUCYTOSINE (5-FC)
• Pyrimidine antimetabolite, narrow-
spectrum fungistatic
• Water soluble
• Oral only,
• Poor protein binding
• CSF conc. ≈ 75% serum conc.

22. • 5-FC
(outside)
Cytosine
permease
enzyme
• 5-FC
(inside)
• 5-FU
(inside)
Inhibits
thymidylate
synthase
• Inhibits
DNA & RNA
synthesis

23. Flucytosine is taken up by fungal cells via the
enzyme cytosine permease.
It is converted intracellularly first to 5-FU and
then to 5-fluorodeoxyuridine monophosphate
(FdUMP) and fluorouridine triphosphate
(FUTP), which inhibit DNA and RNA synthesis,
respectively.

24. Human cells are unable
to convert the parent
drug to its active
metabolites.

25. Clinical use at present is confined to
combination therapy, either with:
 Amphotericin B for cryptococcal
meningitis , or
 Itraconazole for chromoblastomycosis

26. Adverse Effects
• Bone marrow toxicity with anemia,
leukopenia, thrombocytopenia,
(Mammalian bone marrow cell have the
capacity to convert 5-FC to 5-FU)
• GI disturbances
• Mild & reversible liver dysfunction

27. KEY POINTS
• Since this is a narrow-spectrum fungistatic, it
is mainly used as an adjuvant drug & not
used as a sole therapy.
• CSF penetration is excellent, hence it is
combined with AMB in fungal meningitis.

28. Azoles

29. Azoles
Imidazoles
Ketoconazole
Miconazole
Clotrimazole
Triazoles
Itraconazole
Fluconazole
Voriconazole
Posaconazole

30. Mechanism of Action
Inhibition of
fungal
cytochrome
P450 enzymes
Reduction of
ergosterol
synthesis

32. Clinical Use
BROAD SPECTRUM OF ACTIVITY –
Candida,
Cryptococcus,
Blastomyces,
Histoplasma,
Coccidiodes ,
Dermatophytes

33. Adverse Effects
Relatively nontoxic.
Minor GI upset
Abnormalities in liver enzymes
(inhibit cytochrome P450 enzymes)
Very rarely, clinical hepatitis

34. KETOCONAZOLE
•(older, more toxic, replaced by itraconazole, but less
costly)
•The first oral azole introduced into clinical use.
•It is less selective for fungal P450 than are the newer
azoles.
•Absorption variable (better in acidic medium)
•Penetration in brain & CSF is poor
•In high doses inhibits adrenocortical steroids and
testosterone synthesis, resulting in gynecomastia in
some males.

35. ITRACONAZOLE
•Broad-spectrum antifungal with fungistatic
action
•MOA: Inhibits fungal ergosterol synthesis like
other azoles
• Drug absorption is increased by food and by
low gastric ph.
•Penetration of drug in brain & CSF is poor.
• Much more selective than ketoconazole

36. FLUCONAZOLE
Broad-spectrum Fungicidal drug;
•It is also somewhat effective against some
Gram-positive & anaerobic bacteria
•Of the orally administered fluconazole 94% is
absorbed;
•Penetration in brain & CSF is good, hence
used for cryptococcal meningitis

37. Posaconazole
The newest triazole
It is the broadest spectrum member of
the azole family.
It is the only azole with significant
activity against the agents of zygomycosis
and mucormycosis.

38. ECHINOCANDINS
Caspofungin
Micafungin
Anidulafungin

39. ECHINOCANDINS
The newest class of antifungal .
Active against candida and
aspergillus, but not c neoformans or
the agents of zygomycosis and
mucormycosis.

40. Mechanism of Action
Inhibit the synthesis
of B glucan in the
fungal cell wall
Disruption of the
fungal cell wall
and cell death.

41. Adverse Effects
Extremely well tolerated, Minor GI
side effects
Flushing
 Elevated liver enzymes
(caspofungin + cyclosporine).
Histamine release during IV
infusion.

43. Systemic antifungal drugs for
Mucocutaneous infections

44. GRISEOFULVIN
Very insoluble, fungistatic
 Derived from a species of
penicillium.
 Better absorption when given
with fatty foods.

45. • It is deposited in newly forming skin
where it binds to keratin, protecting the
skin from new infection.
• Interferes with spindle formation in
dividing cells and therefore with mitosis

46. Adverse effects
• Allergic reaction
• photosensitivity
• Hepatitis
• Teratogenesis

47. Terbinafine
• Synthetic allylamine.
• Orally Active.
• Dermatophytoses, especially
onychomycosis .
• Keratophilic , fungicidal.

48. It interferes with
ergosterol
biosynthesis by:
Inhibiting the fungal
enzyme squalene
epoxidase
Accumulation of the
sterol squalene,

49. • Like the azole drugs, it interferes with
ergosterol biosynthesis, but rather than
interacting with the P450 system, terbinafine
inhibits the fungal enzyme squalene
epoxidase.
• This leads to the accumulation of the sterol
squalene, which is toxic to the organism.

50. Adverse effects
Rare, mild, self-limiting
GI upset
Rash
Pruritis
Headache.

51. Topical antifungal
therapy

52. NYSTATIN
• Only used topically: creams, ointments,
suppositories, and other
• Acts as amphotericin B
• It is not absorbed , unpleasant taste.
• Local candidal infections, oropharyngeal
thrush, vaginal candidiasis.
• adverse effects are rare.

53. TOPICAL AZOLES
• Clotrimazole , Miconazole;
• Vulvovaginal candidiasis, oral thrush ,
dermatophytic infections, including tinea
corporis, tinea pedis, and tinea cruris.
• Absorption is negligible, and adverse effects
are rare.
• Topical and shampoo forms of ketoconazole
for seborrheic dermatitis and pityriasis
versicolor.

54. TOPICAL ALLYLAMINES
• Terbinafine and Naftifine
• Both are effective for treatment of tinea
cruris and tinea corporis.
• MOA: Inhibits the squalene epoxidase, leading to
accumulation of intrcellular squalene & deficient
ergosterol synthesis with subseqent fungal cell
death.
• Terbinafine concentrates in skin and
especially at nail beds, making it quite useful
for fungal infection of nails

57. GOOD LUCK
SAMIR EL ANSARY
ICU PROFESSOR
AIN SHAMS
CAIRO
elansarysamir@yahoo.com