Current & newer anti-fungal therapies

Current & newer anti-fungal therapies - CURRENT AND...

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CURRENT AND NEWER ANTI-FUNGAL THERAPIES- MECHANISMS, INDICATIONS, LIMITATIONS AND PROBLEMS Dr AMIT RAODEO DM SEMINAR
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Introduction ± The incidence of invasive fungal infections in critically ill intensive care unit (ICU) and surgical patients has been increasingly recognized. ± Invasive fungal infections are associated with crude mortality rates of 30–40%. ± Often recognized and treated late. ± Ampho B was initially considered gold standard. ± With the introduction of newer antifungals, the horizon has widened.
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Antifungal drugs and mechanism of action Class of drug Examples Mechanism Of action 1. Polyenes Amphotericin B Inserts into the fungal membrane in close association with ergosterol. The subsequent formation of porin channels leads to loss of transmembrane potential and impaired cellular function 2. Azoles Fluconazole, itraconazole, voriconazole etc. Inhibition of the C14 alpha demethylation of lanosterol in fungi, which interfere with the synthesis of ergosterol in the fungal cell membrane 3. Echinocandins Caspofungin, mivafungin Inhibit the synthesis of beta1,3-D glucan, which is integral to the structure and function of the fungal cell wall 4 Flucytosine Inhibits cellular DNA and RNA synthesis
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Conventional antifungal drugs ± Fluconazole ± Itraconazole ± Amphotericin B
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Empirical antifungal therapy for febrile neutropenia YEAR ANTIFUNGAL COMPARATOR SAMPLE SIZE ENDPOINT OUTCOME 1982 AmB vs Placebo 52 Infection Favors AmB 1989 AmB vs Placebo 132 Defervescence Favors AmB 1996 AmB vs FLU 112 Defervescence Equivalence; Safety favors FLU N Engl J Med 2002;346:278-280
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Empirical antifungal therapy for febrile neutropenia Year Antifungal comparator Sample size Endpoint Outcome 1998 AmB Vs FLU 106 Composite Equivalence;Safety favours FLU 1999 AmB Vs L-AmB 702 Composite Equivalence;Secondary analysis favours AmB 2000 AmB Vs FLU 317 Composite Equivalence; Safety favours FLU 2000 L-AmB Vs ABLC 204 Absence of toxic effects Favours L-AmB 2001 AmB Vs ITRA 384 Composite Equivalence; Secondary analysis favours ITRA N Engl J Med 2002;346:278-280
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Comparison of conventional antifungal drugs in invasive aspergillosis 0 10 20 30 40 50 60 Amphotericin AmB to Itraconazole Itraconazole Response (Overall) Response (Severely Immunosuppressed) 32% 24% 54% 41% 57% 40%* Retrospective analysis of 595 patients with definite or probable invasive aspergillosis Medicine 2000;79:250-260
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Lipid-Associated Amphotericin B alone versus in Combination with myograb in Patients with Invasive Candidiasis ± Myograb is an antibody-Based inhibitor of Heat Shock Protein 90 ± Hsp90 is a molecular chaperone present in the fungal cell wall and extracellular material ± Addition of myograb to conventional ampho B improves survival as well as culture conversion rate ± Mycograb was well tolerated ± Hsp90 inhibitors not only have direct antifungal activity, but they may also prevent fungi from developing resistance to fluconazole or caspofungin Clinical Infectious Diseases 2006; 42:1404–13
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Role of itraconazole in post TB aspergilloma and CNPA ± Patients suffering from aspergillosis treated with
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This note was uploaded on 12/03/2011 for the course MEDICINE 350 taught by Professor Dr.aslam during the Winter '07 term at Medical College.

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Current & newer anti-fungal therapies - CURRENT AND...

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