Antifungal drug resistance..............

Antifungal resistivity of drugs

1. DRUG RESISTANCE IN ANTIFUNGAL PRESENTED BY: SATHYA G 23BT045 I- BIOTECHNOLOGY d

2. INTRODUCTION

3. Introduction Pathogenic fungi of animals and humans are generally filamentous molds or intracellular yeasts. The fungal cell wall contains chitin and polysaccharides making it rigid, and acts as a barrier to drug penetration. The cell membrane contains ergosterol, which influences the efficacy and the risk of drug resistance. Most antifungal agents are fungistatic with infection-clearance largely dependent on host response. 3

4. FUNGI Fungi may be classified as Yeasts : Blastomyces , candida, histoplasma , coccidioides,cryptococcus . Moulds : Aspergillus spp. , Dermatophytes Clinically classified as : Superficial mycosis Deep (systemic) mycosis 5

5. FUNGI 6

6. Types of fungal infections 7 Mucocutaneous (superficial) infections: Dermatophytes: cause infection of skin, hair, and nails e.g. tinea capitis (scalp), tinea cruris (groin), tinea pedis (foot), onychomycosis (nails).

7. Types of fungal infections 8 Yeasts : cause infections of moist skin and mucous membranes e.g. Candida albicans causing oral, pharyngeal, vaginal, & bladder infections

8. Types of fungal infections 9 Systemic mycoses: are fungal infections affecting internal organs. It occurs in immunocompromized patients e.g. cryptococcosis , and aspergillosis (lung).

9. CLASSIFICATION OF ANTIFUNGALS

10. Classification of antifungal drugs 11 Drugs for mucocutaneous infections : Systemic drugs Azoles : Fluconazole, Itraconazole , Voriconazole . Griseofulvin Terbinafine

11. Classification of antifungal drugs 12 Topical drugs Azoles : Ketoconazole, Miconazole , Clotrimazole , Tioconazole , etc. Nystatin Terbinafine . Other drugs : Tolnaftate , Ciclopirox, Naftifine , Whitfield ointment, Gentian violet, Castellani paint, Tincture iodine.

12. Classification of antifungal drugs 13 Drugs for Systemic infections : : Azoles : Fluconazole, Itraconazole , Voriconazole . Amphotericin-B Flucytosine Caspofungin

13. Azoles 14 Mechanism of action Azoles inhibit fungal cytochrome P450 ( 14 α demthylase ) necessary for ergosterol synthesis, a major component of fungal cell membrane. This will alter membrane permeability and disrupt its function. are broad spectrum fungistatic against many dermatophytes and candida.

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15. Azoles 16 Therapeutic uses Superficial fungal infections : [ketoconazole – itraconazole – miconazole ] Dermatophytes infection of the skin (tinea), hair, and nails (onychomycosis): For skin infection: treatment continued for 2-4 weeks. For hair infection: treatment continued for 6-8 weeks. For nail infection: treatment continued for 3-6 months. Mucocautaneous candidiasis : oropharyngeal, vulvovaginal, etc.

16. Azoles 17 Systemic fungal infections : [ itraconazole – fluconazole – voriconazole ] Itraconazole (orally or IV) is the drug of choice for systemic blastomycosis . Fluconazole (orally or IV) is the drug of choice for systemic candidiasis, and cryptococcal meningitis (because it the only azole that can cross to CSF with good concentration ). Voriconazole is the drug of choice for inVasive aspergillosis of the lung.

17. Griseofulvin 18 Mechanism of action Griseofulvin binds to microtubules and prevents spindle formation and mitosis in fungi. It is fungistatic and requires long duration of therapy. The drug binds to keratin structures and accumulates in skin, hair, and nails.

18. DRUG RESISTANCE IN ANTIMICROBIAL

19. FLEMING AND PENICILLIN . 20

20. HISTORY In his 1945 Nobel prize lecture, Fleming himself warned of the danger of resistance – “ It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body and by exposing his microbes to non- lethal quantities of the drug make them resistance. ” . 21 Sir Alexander Fleming

21. INTRINSIC RESISTANCE It occurs naturally. 1. Lack target: No cell wall ; innately resistance to penicillin. 2. Innate efflux pumps: Drug blocked from entering cell or export of drugs (does not achieve adequate internal concentration) Eg : E.coli , P.aeruginosa 3. Drug inactivation: Cephalosporinase in Klebsiella . 22

22. ACQUIRED RESISTANCE Mutations: It refers to the change in DNA structure of the gene. Occurs at a frequency of one per ten million cells. Often mutants have reduced susceptibility Eg : Mycobacterium tuberculosis , Mycobacterium lepra .. . 23

23. Mechanisms of Gene Transfer Transfer of r-genes from one bacterium to another 1. Conjugation 2. Transduction 3. Transformation Transfer of r-genes between plasmids within bacterium 1. By transposons 2. By integrons . 24

24. Transfer of r-genes Conjugation : Main mechanism for spread of resistance . The conjugative plasmids make a connecting tube between the 2 bacteria through which plasmid itself can pass. Transduction : Less common method The plasmid DNA enclosed in a bacteriophage is transferred to another bacterium of same species. Seen in Staphylococci , Streptococci. Transformation : Least clinical problems. Free DNA is picked up from the environment ( i.e ; From a cell belonging to closely related or same strain. . 25

25. GENE TRANSFER METHOD The Power of PowerPoint | thepopp.com 26

26. I.TRANSPOSONS . 27 Transposons are sequences of DNA that can move around different positions within the genome of single cell. The donor plasmid containing the transposons , co-integrate with acceptor plasimds . They can replicate during co-integration. Both plasmids then separate and each cointains the r-gene carrying the transposons .

27. 2.INTEGRONS Integron is a large mobile DNA can spread Multi-drug resistance. Each integron is a packed with multiple gene casettes , each consisting of a resistance gene attached to a small recognition site. These genes encode several bacterial functions including resistance and virulence. They cannot promote self transfer. . 28

28. Drug Mechanism of Resistance Pencillins & Cephalosporiins B Lactamase cleavage of the Blactam ring Aminoglycosides Modification by phosphorylating , adenylating and acetylating enzymes Chloramphenicol Modificatio by acetylytion Erythromycin Change in receptor by methylation of r RNA Tetracycline Reduced uptake / increased export Sulfonamides Active export out of the cell & reduced Affinity of enzymes

29. CONCLUSION Anti microbial resistance is an emerging global treat. Strategies to prevent development of antimicrobial resistance should be devised. Judicious use of antimicrobial agents by health care professionals & general populations. Preventing un-judicious use of antibiotics in animal husbandry and farming practices. Avoiding incorporation of antibiotics in commercial cleansing products. Proper pharmaceutical waste management. . 30

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