Antimicrobial Drugs

1. Antimicrobial Drugs • Chemotherapy The use of drugs to treat a disease • Antimicrobial drugs Interfere with the growth of microbes within a host • Antibiotic Substance produced by a microbe that, in small amounts, inhibits another microbe • Selective toxicity A drug that kills harmful microbes without damaging the host

2. 1928 – Fleming discovered penicillin, produced by Penicillium. • 1940 – Howard Florey and Ernst Chain performed first clinical trials of penicillin. Figure 20.1

3. Table 20.1

4. ANTIMICROBIAL SENSITIVITY TESTS @ Used to select effective drugs for treatment. @ Not performed on commensals or contaminants • @ This misleads physician and patient to receive unnecessary therapy • @ Such therapy leads to side-effects & resistance of pathogens. • @ Used to identify organism if it has a characteristic sensitivity pattern.

5. LIMITATIONS: • Measure in vitro not in vivo drug activity. • Selection of best drug depends on: • a) Patient clinical condition • b) Type and site of infection. • c) History of drug hypersensitivity. • 3.Drug activity : absorption, diffusion in tissues, metabolism, excretion, toxicity, effect on patient normal flora, • are not known by sensitivity.

6. Table 20.2

7. The Action of Antimicrobial Drugs • Broad-spectrum • Superinfection • Bactericidal • Bacteriostatic

8. The Action of Antimicrobial Drugs Figure 20.2

9. The Action of Antimicrobial Drugs Figure 20.4

10. Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis • Penicillin • Natural penicillins • Semisynthetic penicillins

11. Penicillins Figure 20.6

12. Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis • Penicillin • Penicilinase-resistant penicillins • Extended-spectrum penicillins • Penicillins + -lactamase inhibitors • Carbapenems • Monobactam

13. Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis Figure 20.8

14. Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis • Cephalosporins • 2nd, 3rd, and 4th generations more effective against gram-negatives Figure 20.9

15. Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis • Polypeptide antibiotics • Bacitracin • Topical application • Against gram-positives • Vancomycin • Glycopeptide • Important "last line" against antibiotic resistant S. aureus

16. Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis • Antimycobacterium antibiotics • Isoniazid (INH) • Inhibits mycolic acid synthesis • Ethambutol • Inhibits incorporation of mycolic acid

17. Antibacterial Antibiotics Inhibitors of Protein Synthesis • Chloramphenicol • Broad spectrum • Binds 50S subunit, inhibits peptide bond formation • Aminoglycosides • Streptomycin, neomycin, gentamycin • Broad spectrum • Changes shape of 30S subunit

18. Antibacterial Antibiotics Inhibitors of Protein Synthesis • Tetracyclines • Broad spectrum • Interferes with tRNA attachment • Macrolides • Gram-positives • Binds 50S, prevents translocation • Erythromycin • Gram-positives • Binds 50S, prevents translocation

19. Antibacterial Antibiotics Inhibitors of Protein Synthesis • Streptogramins • Gram-positives • Binds 50S subunit, inhibits translation • Synercid • Gram-positives • Binds 50S subunit, inhibits translation • Oxazolidinones • Linezolid • Gram-positives • Binds 50S subunit, prevents formation of 70S ribosome

20. Antibacterial Antibiotics Injury to the Plasma Membrane • Polymyxin B • Topical • Combined with bacitracin and neomycin in over-the-counter preparation

21. Antibacterial Antibiotics Inhibitors of Nucleic Acid Synthesis • Rifamycin • Inhibits RNA synthesis • Antituberculosis • Quinolones and fluoroquinolones • Ciprofloxacin • Inhibits DNA gyrase • Urinary tract infections

22. Antibacterial Antibiotics Competitive Inhibitors • Sulfonamides (Sulfa drugs) • Inhibit folic acid synthesis • Broad spectrum Figure 5.7

23. Figure 20.13

24. Antifungal DrugsInhibition of Ergosterol Synthesis • Polyenes • Amphotericin B • Azoles • Miconazole • Triazoles • Allylamines Figure 20.15

25. Antifungal DrugsInhibition of Cell Wall Synthesis • Echinocandins • Inhibit synthesis of -glucan • Cancidas is used against Candida and Pneumocystis

26. Antifungal DrugsInhibition of Nucleic Acids • Flucytocine • Cytosine analog interferes with RNA synthesis • Pentamidine isethionate • Anti-Pneumocystis; may bind DNA

27. Antifungal DrugsInhibition of Microtubules (Mitosis) • Griseofulvin • Used for superficial mycoses • Tolnaftate • Used for athlete's foot; action unknown

28. Antiviral DrugsNucleoside and Nucleotide Analogs Figure 20.16a

29. Antiviral DrugsNucleoside and Nucleotide Analogs Figure 20.16b, c

30. Antiviral DrugsEnzyme Inhibitors • Protease inhibitors • Indinavir • HIV • Inhibit attachment • Zanamivir • Influenza • Inhibit uncoating • Amantadine • Influenza • Interferons prevent spread of viruses to new cells • Viral hepatitis

31. Antiprotozoan Drugs • Chloroquine • Inhibits DNA synthesis • Malaria • Diiodohydroxyquin • Unknown • Amoeba • Metronidazole • Damages DNA • Entamoeba, Trichomonas

32. Antihelminthic Drugs • Niclosamide • Prevents ATP generation • Tapeworms • Praziquantel • Alters membrane permeability • Flatworms • Pyantel pamoate • Neuromuscular block • Intestinal roundworms

33. Antihelminthic Drugs • Mebendazole • Inhibits nutrient absorption • Intestinal roundworms • Ivermectin • Paralyzes worm • Intestinal roundworms

34. Disk-Diffusion Test Figure 20.17

35. E Test Figure 20.18

36. MIC Minimal inhibitory concentration • MBC Minimal bactericidal concentration

37. Broth Dilution Test Figure 20.19

38. Figure 20.20

39. Antibiotic Resistance • A variety of mutations can lead to antibiotic resistance. • Mechanisms of antibiotic resistance 1. Enzymatic destruction of drug 2. Prevention of penetration of drug 3. Alteration of drug's target site 4. Rapid ejection of the drug • Resistance genes are often on plasmids or transposons that can be transferred between bacteria.

40. Antibiotic Resistance • Misuse of antibiotics selects for resistance mutants. Misuse includes: • Using outdated, weakened antibiotics • Using antibiotics for the common cold and other inappropriate conditions • Use of antibiotics in animal feed • Failure to complete the prescribed regimen • Using someone else's leftover prescription

41. Effects of Combinations of Drugs • Synergism occurs when the effect of two drugs together is greater than the effect of either alone. • Antagonism occurs when the effect of two drugs together is less than the effect of either alone.

42. Effects of Combinations of Drugs Figure 20.22

43. The Future of Chemotherapeutic Agents • Antimicrobial peptides • Broad spectrum antibiotics from plants and animals • Squalamine (sharks) • Protegrin (pigs) • Magainin (frogs) • Antisense agents • Complementary DNA or peptide nucleic acids that binds to a pathogen's virulence gene(s) and prevents transcription

44. TECHNIQUES: • Mainly two: • Diffusion technique. • Dilution technique.

45. DIFFUSION SENSITIVITY TECHNIQUE: • @ Used in routine sensitivity testing. • @ A disc of filter paper is impregnated with a known volume & concentration of a drug & placed on an agar medium inoculated with a test organism.

46. Control organisms are inoculated: @ On same plate (Stokes technique). @ On a separate plate (Kirby-Bauer technique). Drug diffuses into medium.

47. @ After an overnight incubation, culture is examined for areas of no growth (inhibition zones) around discs: • Sensitive bacteria are inhibited at a distance from disc. • Resistant bacteria grow up to the edge of disc.

48. @ In Stokes technique: • inhibition zone is compared directly with that of control . • @ In Kirby-Bauer technique: • zone is measured & compared against a previously prepared scale that correlates zone size with MIC.

49. @ MIC is the minimum drug concentration required to inhibit bacterial multiplication under standard conditions. @ It is measured by the dilution sensitivity technique. @ Inhibition zone increases when MIC decreases.

50. Inhibition zones vary in size due to: • Difference in molecular structures of drugs (larger zones are obtained when drugs diffuse rapidly in medium). • When bacterial growth is heavy (zones are smaller, & vice versa) . • Factors affecting the medium: • (volume, moisture, pH, & constituents). • 4.Factors affecting the disc: (drug concentration, storage, & application).