antifungal chemotherapy
TRANSCRIPT
INSTITUTE OF HEALTH TECHNOLOGY, DHAKADepartment of Laboratory Medicine
BSc in Health Technology (Laboratory)- 1st Year
MYCOLOGY Lecture No. 8 (Antifungal Chemotherapy)
By
Sk. MIZANUR RAHMANLecturer, Mycology
MS in Biotechnology & Genetic Engineering (UODA)MS in Microbiology (SU)
Antifungal Chemotherapy
The treatment of disease by the use of chemical substances, especially the treatment of fungal diseases by cytotoxic and other drugs.
Chemotherapy Types1. Prophylactic – Anti-fungal agents at, or near,
the time of chemotherapy. Posaconazole now approved.2. Empirical – Start therapy when patient at risk,
i.e., fever and/or infiltrate without response to anti-bacterials.
3. Pre-emptive –When there is some additional evidence of fungal infection (serology, isolate, etc.)
Antifungal agents targeted towards:
Inhibition of fungal cell wall synthesis – caspofungin is a -glucan synthesis inhibitor; several more compounds are under investigation
Inhibition of fungal cell membrane synthesis – ergosterol is the target (cell membranes of fungi and mammals contain different sterols): polyenes, azoles, triazoles, alkylamines
Inhibition of cell division – microtubule effects: griseofulvin; DNA: flucytosine.
Biochemical Targets for Antifungal Chemotherapy
Antifungal Agents: Families
• Azoles
• Allylamines
• Benzofurans
• Polyenes
• Pyrimidines
• Lipopeptides
Imidazoles Triazoles
Azole Antifungals for Systemic Infections
• Ketoconazole (Nizoril)• Itraconazole (Sporanox)• Fluconazole (Diflucan)• Voriconazole (Vfend)
Imidazole
Triazoles
“2nd generationtriazole”
Fluconazole Ketoconazole
The Fungal Cell Wall
mannoproteins
1,6glucans
1,3
chitin
ergosterol
1,3 glucansynthase
Cellmembrane
Atlas of fungal Infections, Richard Diamond Ed. 1999Introduction to Medical Mycology. Merck and Co. 2001
Antifungal Agents- Sites of action
EchinocandinsInhibit fungal cell wallbiosynthesis
GriseofulvinInhibits mitoticspindle formation
What are the targets for antifungal therapy?
Cell membraneFungi use principally ergosterol instead of cholesterol
Cell WallUnlike mammalian cells, fungi have a cell wall
DNA SynthesisSome compounds may be selectively activated by fungi, arresting DNA synthesis.
Atlas of fungal Infections, Richard Diamond Ed. 1999Introduction to Medical Mycology. Merck and Co. 2001
Cell Membrane Active Antifungals
Cell membrane • Polyene antibiotics - Amphotericin B, lipid formulations - Nystatin (topical)
• Azole antifungals - Ketoconazole - Itraconazole - Fluconazole - Voriconazole - Miconazole, clotrimazole (and other topicals)
Cell Wall Active AntifungalsCell membrane • Polyene antibiotics • Azole antifungals
DNA/RNA synthesis • Pyrimidine analogues - Flucytosine
Cell wall • Echinocandins -Caspofungin acetate (Cancidas)
Cell Wall Active Antifungals
Cell membrane • Polyene antibiotics • Azole antifungals
DNA/RNA synthesis • Pyrimidine analogues - Flucytosine
Cell wall • Echinocandins -Caspofungin acetate (Cancidas)
Atlas of fungal Infections, Richard Diamond Ed. 1999Introduction to Medical Mycology. Merck and Co. 2001
Azoles
• Azoles
• Causes Inhibition of C-14 α demethylase, (an enzyme required for the synthesis of ergosterol) by binding to cytochrome P450
Imidazoles Triazoles
Allyamines
• Inhibits squalene epoxidase, an enzyme essential for synthesis of ergosterol
• Drug acculmulates in nails, skin and fat
• Very useful for nail infections
Polyenes
• Amphotericin, nystatin• Antifungal activity by
binding to membrane sterols such as ergosterol and they increase membrane permeability and leads to cell death
Amphotericin• Numerous forms• Pastilles, Parenteral forms: amphotericin B,
deoxycholate form, colloidal form, Liposomal form• Toxicity: Dose dependent reduction in GFR, by direct
vasoconstritive effect on afferent renal arterioles, destruction of renal tubular cells and basement membrane and loss of functioning units
• Also nausea .vomiting, phlebitis and ACUTE REACTION: fever,chills,tachyapnea
Pyrimidines• Fluorine analogue of a
normal cell constituent cytosine
• Demination results in 5-fluorouracil, to 5-flurodeoxyuridylic acid monophosphate, a non-competitive inhibitor of thymidylate synthetase
• Used particularly in crytococcal meningitis-74% of serum levels
Benzofurans
• Griseofulvin• Inhibits nucleic acid synthesis, macrotubule
formation and chitin formation• Active against ringworm, not candidia or tinea
versicolor
Lipopeptides
• Echinocandins, derivatives of pneumocandin BO
• Inhibition of ß 1 ,3 glucans in the fungal wall• Active candida, aspergillosis and pneumocystis
carinii