1. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Begumisa Magyezi Antimicrobial Chemotherapy: An Introduction

2. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Antimicrobial Drugs ChemotherapyThe use of drugs to treat a disease Antimicrobial drugsInterfere with the growth of microbes within a host AntibioticSubstance produced by a microbe that, in small amounts, inhibits another microbe Selective toxicityA drug that kills harmful microbes without damaging the host

3. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Definition of key terms Antibiotic spectrum—Range of activity of an antimicrobial against bacteria. A broad-spectrum antibacterial drug can inhibit a wide variety of gram-positive and gram-negative bacteria, whereas a narrow- spectrum drug is active only against a limited variety of bacteria. Bacteriostatic activity—-The level of antimicrobial activity that inhibits the growth of an organism. This is determined in vitro by testing a standardized concentration of organisms against a series of antimicrobial dilutions. The lowest concentration that inhibits the growth of the organism is referred to as the minimum inhibitory concentration (MIC). Bactericidal activity—The level of antimicrobial activity that kills the test organism. This is determined in vitro by exposing a standardized concentration of organisms to a series of antimicrobial dilutions. The lowest concentration that kills 99.9% of the population is referred to as the minimum bactericidal concentration (MBC).

4. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Definition of key terms Antibiotic combinations—Combinations of antibiotics that may be used: i.to broaden the antibacterial spectrum for empiric therapy or the treatment of polymicrobial infections, ii.to prevent the emergence of resistant organisms during therapy, and iii.to achieve a synergistic killing effect. Antibiotic synergism—Combinations of two antibiotics that have enhanced bactericidal activity when tested together compared with the activity of each antibiotic. Antibiotic antagonism—Combination of antibiotics in which the activity of one antibiotic interferes With the activity of the other (e.g., the sum of the activity is less than the activity of the individual drugs). Beta-lactamase—An enzyme that hydrolyzes the beta-lactam ring in the beta-lactam class of antibiotics, thus inactivating the antibiotic. The enzymes specific for penicillins and cephalosporins are the penicillinases and cephalosporinases, respectively.

5. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings History of Antibiotics 1910 - Paul Ehlrich “magic bullets” - chemicals with selective toxicity 1928 – Alexander Fleming discovered penicillin, produced by Penicillium mold. 1940 – Howard Florey and Ernst Chain performed first clinical trials of penicillin. Figure 20.1

6. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Table 20.1

7. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Table 20.2 Spectrum of activity

8. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings The Action of Antimicrobial Drugs Broad-spectrum Narow-spectrum Superinfection Bactericidal Bacteriostatic

9. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Effect of antimicrobial agents on microbes

10. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings The Action of Antimicrobial Drugs Figure 20.2

11. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings The Action of Antimicrobial Drugs Figure 20.4

12. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Penicillin Natural penicillins Semisynthetic penicillins Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis

13. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Penicillins Figure 20.6

14. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Penicillin Penicilinase-resistant penicillins Extended-spectrum penicillins Penicillins +  -lactamase inhibitors Carbapenems Monobactam Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis

15. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis Figure 20.8

16. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Cephalosporins 2 nd, 3 rd, and 4 th generations more effective against gram-negatives Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis Figure 20.9

17. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Polypeptide antibiotics Bacitracin Topical application Against gram-positives Vancomycin Glycopeptide Important "last line" against antibiotic resistant S. aureus Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis

18. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Antimycobacterium antibiotics Isoniazid (INH) Inhibits mycolic acid synthesis Ethambutol Inhibits incorporation of mycolic acid Carbapenems Imipenen has widest spectrum of activity of ß-lactam drugs Monobactams Aztreonam has excellen activity against gr-ve but not gr+ve or anaerobes Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis

19. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Chloramphenicol Broad spectrum Binds 50S subunit, inhibits peptide bond formation Aminoglycosides Streptomycin, neomycin, gentamycin Broad spectrum Changes shape of 30S subunit Antibacterial Antibiotics Inhibitors of Protein Synthesis

20. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Tetracyclines Broad spectrum Interferes with tRNA attachment Macrolides (azithromycin, clarithromycin) Gram-positives Binds 50S, prevents translocation Erythromycin Gram-positives Binds 50S, prevents translocation Antibacterial Antibiotics Inhibitors of Protein Synthesis

21. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Streptogramins Gram-positives Binds 50S subunit, inhibits translation Synercid Gram-positives Binds 50S subunit, inhibits translation Linezolid Gram-positives Binds 50S subunit, prevents formation of 70S ribosome Antibacterial Antibiotics Inhibitors of Protein Synthesis

22. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Polymyxin B Topical Combined with bacitracin and neomycin in over- the-counter preparation Antibacterial Antibiotics Injury to the Plasma Membrane

23. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Rifamycin Inhibits RNA synthesis Antituberculosis Quinolones and fluoroquinolones Ciprofloxacin Inhibits DNA gyrase Urinary tract infections Damage growing bones and cartilages Antibacterial Antibiotics Inhibitors of Nucleic Acid Synthesis

24. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Antibacterial Antibiotics Inhibitors of Nucleic Acid Synthesis Inhibition of precursor synthesis Sulfonamides Trimethoprim Inhibition of DNA synthesis Quinolones Flucytosine Inhibition of mRNA synthesis Rifampin

25. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Sulfonamides (Sulfa drugs) Inhibit folic acid synthesis Broad spectrum Antibacterial Antibiotics Competitive Inhibitors Figure 5.7

26. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Figure 20.13 P-aminobenzoic acid Inhibition of folic acid synthesis

27. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Alternation of bacterial cell membranes Polymyxins (E) Mainly active against gr-ve “P. aeruginosa” Alteration of fungal cell membranes Amphotericin B “high affinity for ergosterol” (polyene) Nystatin “topically, Candida” Azoles “act by inhibiting ergosterol synthesis” „ e.g. Fluconazole, ketoconazole, itraconazole, clotrimazole and miconazole“ Alternation of cell membrane function

28. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Used to prevent diseases Prior to surgery Immunocompromised patients Against certain pathogens Chemoprophylaxis

29. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Live, nonpathogenic bacteria Providing colonization resistance Enhancing the immune system against pathogen Reduce the inflammation response against the pathogen e.g. Lactobacillus rahmnosus Probiotics

30. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Polyenes Amphotericin B Nystatin Azoles Miconazole Triazoles Allylamines Antifungal Drugs Inhibition of Ergosterol Synthesis Figure 20.15

31. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Antifungal Drugs Inhibition of Nucleic Acids Flucytocine Cytosine analog interferes with RNA synthesis Pentamidine isethionate Anti-Pneumocystis; may bind DNA

32. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Griseofulvin Used for superficial mycoses Tolnaftate Used for athlete's foot; action unknown Antifungal Drugs Inhibition of Microtubules (Mitosis)

33. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Antiviral Drugs Nucleoside and Nucleotide Analogs Figure 20.16a

34. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Antiviral Drugs Nucleoside and Nucleotide Analogs Figure 20.16b, c

35. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Protease inhibitors Indinavir, Saquinavir, ritonavir,nelfinavir HIV Inhibit attachment Zanamivir (neuraminidase inhibitor) Influenza (Influenza A & B viruses) Inhibit uncoating Amantadine Influenza Interferons prevent spread of viruses to new cells Viral hepatitis Antiviral Drugs Enzyme Inhibitors

36. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Antihelminthic Drugs Niclosamide Prevents ATP generation Tapeworms Praziquantel Alters membrane permeability Flatworms Pyantel pamoate Neuromuscular block Intestinal roundworms

37. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Disk-Diffusion Test Figure 20.17

38. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings E Test Figure 20.18

39. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings MIC Minimal inhibitory concentration MBC Minimal bactericidal concentration Serum Bactericidal Activity ß-Lactamase Production Antibiotic Sensitivity Testing

40. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Broth Dilution Test Figure 20.19

41. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings 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. Antibiotic Resistance

42. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Overuse or 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 Antibiotic Resistance

43. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings 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. Indifference occurs when the effect of two drugs together is almost the same as the effect of either alone. Effects of Combinations of Drugs

44. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Effects of Combinations of Drugs Figure 20.22