1. Chijioke Onejeme 1

2. Lecture Objectives  Discuss the structure and mechanism of action of various antibiotic classes: Cell wall inhibitors Sulfonamides Macrolides Tetracyclines Fluoroquinolones Metronidazole  Understand the principles of antimicrobial resistance and the pharmacist’s role in combating it  Discuss counseling points and other important tips to provide to patients when administering antimicrobial therapy 2

3. Beta-lactams 3

4.  Penicillins  Cephalosporins  Carbapenums  Monobactams 4 http://www.life.umd.edu/classroom/bsci424/Images/PathogenImages/Bet aLactam.gif

5. Structure and Reactivity  Beta-lactam nucleus is responsible for antimicrobial activity  Degradation of beta-lactam ring (by beta- lactamases) or other means results in a loss of function 5

6. Bacterial Cell Wall Review  Bacteria constantly remodel their peptidoglycan cell walls ○ Simultaneously building and breaking down the wall at different portions as the cell grows and divides  Transpeptidase cross-links the oligopeptide side-chains 6

7. Peptidoglycan Structure 7

8. Mechanism of Action  Beta-lactams irreversibly bind to specific sites on transpeptidase (penicillin- binding proteins), disabling the enzyme’s ability to cross-link peptidoglycan.  This weakens the cell wall, and causes the bacteria to rupture from osmotic pressure 8

9. Mechanism of Action 9 http://www.antibioticslist.com/images/design/penicillin_img.gif

10. Penicillins  Discovered as natural products from the mold Penicillium rubrum Alexander Fleming  Among the earliest and still most widely used antibiotics 10

11. Penicillin Structure 11 www.microbiologyprocesses.blogspot.com

12. Penicillins  Penicillin G  Penicillin V  Oxacillin  Dicloxacillin  Nafcillin  Amoxicillin  Ampicillin  Methicillin*  Piperacillin  Ticarcillin 12

13. Patient Counseling Tip  Take penicillin-VK with food to reduce the GI side effects (diarrhea, nausea) 13

14. Cephalosporins  Originally isolated from the fungus Acremonium sp.  Widely used in the prophylaxis and treatment of infections  5 generations—some variance in antimicrobial coverage and side effects between them 14

15. Cephalosporin Structure 15 http://withfriendship.com/images/h/39377/Cephalosporin-picture.gif

16. Cephalosporins Cefazolin Cephalexin 1 st Generation Cefuroxime Cefoxitin 2 nd Generation Ceftriaxone Cefdinir 3 rd Generation Cefipime 4 th Generation Ceftobiprole 5 th Generation 16

17. Patient Counseling Tip  Patients who are allergic to penicillins may also be allergic to cephalosporins. Use caution when administering to these patients or avoid altogether 17

18. Carbapenems  Developed from thienamycin, a natural product from the bacteria Streptomyces cattleya  Very broad spectrum of activity  Only available in IV formulations 18

19. Carbapenem Structure 19 http://upload.wikimedia.org/wikipedia/commons/thumb/a/af/Carba penems_structure.svg/500px-Carbapenems_structure.svg.png

20. Carbapenems ErtapenemImipenem/cilastatin MeropenemDoripenem 20

21. Patient Counseling Tip  Some carbapenems increase the risk of seizures. Use extreme caution and monitoring when administering them to patients who have a history of seizures or are currently taking anti- epileptic medication 21

22. Monobactams  Unique among beta-lactams in that the principle structure consists of only one ring (the beta-lactam)  Only available agent in the US is aztreonam  Structure is a modified derivative of the bacteria Chromobacterium violaceum  One of only a few antibiotics that are available via the inhalation route 22

23. Aztreonam Structure 23 http://upload.wikimedia.org/wikipedia/commons/thumb/4/4d/Aztreonam_str ucture.svg/500px-Aztreonam_structure.svg.png

24. Patient Counseling Tip  There is no documented cross- sensitivity between aztreonam and penicillins. If a patient is allergic to penicillin, aztreonam can still be considered for use. However, caution and monitoring is recommended 24

25. Beta-lactamase Inhibitors Clavulanic acid Sulbactam Tazobactam  Sometimes given with penicillins to counteract bacterial resistance  Inhibit the bacterial enzyme beta- latamase, which breaks open the beta- lactam ring—thus rendering the antibiotic ineffective 25

26. Vancomycin 26

27. Vancomycin  Originally isolated from the soil bacterium Amycolatopsis orientalis  Has a spectrum limited to gram positive organisms 27

28. Vancomycin Structure 28 http://upload.wikimedia.org/wikipedia/commons/thumb/f/f4/Vancomy cin.svg/500px-Vancomycin.svg.png

29. Vancomycin Mechanism of Action  Inhibits proper cell wall synthesis in gram positive bacteria  Binds to terminal D-Ala-D-Ala residues on the oligopeptides protruding from the NAG/NAM backbone This prevents cross-linking (similar to beta- lactams, but by a different mechanism) 29

30. Vancomycin Mechanism of Action 30 http://upload.wikimedia.org/wikipedia/commons/thumb/5/5f/Vancomycin_resist ance.svg/800px-Vancomycin_resistance.svg.png

31. Patient Counseling Tip  Infusion of vancomycin at rates above 1 gram/hour can lead to an immune reaction known as “Red Man Syndrome” 31

32. Summary 32 http://e-learning.perubatan.org/index.php?topic=622.0

33. 33

34. Sulfonamides  The first antimicrobial drugs discovered—launched the antibiotic revolution in medicine  Have a broad antibiotic spectrum  The sulfonamide moiety is found in many other areas of medicine 34

35. Sulfonamide Structure 35 http://upload.wikimedia.org/wikipedia/commons/8/8b/Sulfam ethoxazole.png http://upload.wikimedia.org/wikipedia/commons/5/59/Sulfona mide.png

36. Sulfonamide Mechanism of Action Structural analogs of PABA PABA is necessary for Folic acid synthesis Folic acid is necessary for DNA synthesis Bacteria are unable to replicate 36

37. Sulfonamide Mechanism of Action 37 http://upload.wikimedia.org/wikipedia/commons/thumb/0/09/Sulfa_fo late.svg/1000px-Sulfa_folate.svg.png

38. Sulfonamide Antibiotics  Sulfamethoxazole  Sulfacetamide  Sulfadiazine  Silver Sulfadiazine  Mafenide 38

39. Patient Counseling Tip  Drink a full glass of water when taking each dose of a sulfonamide 39

40. 40

41. Macrolides  Derived from secondary metabolites (polyketides) of bacteria and fungi  Broad spectrum of antimicrobial activity  Activity stems from macrocytic lactone (macrolide) ring 41

42. Macrolide Structure 42 http://upload.wikimedia.org/wikipedia/commons/thumb/6/6 5/Erythromycin_A.svg/500px-Erythromycin_A.svg.png

43. Macrolide Mechanism of Action  Reversibly bind to the P-site on the 50s ribosomal subunit of susceptible bacteria  This inhibits the action of peptidyl transferase, which is responsible for elongation of the growing peptide chain  Bacteria is unable therefore unable to synthesize protein, and will eventually die 43

44. Macrolide Mechanism of Action 44

45. Macrolides  Erythromycin  Clarithromycin  Azithromycin  Telithromycin* ○ a ketolide 45

46. Clindamycin  A lincosamide antibiotic  Structurally dissimilar to macrolides  Similar MOA (binds to 50s subunit) as macrolides 46 http://www.chemicalbook.com/CAS%5CGIF%5C1832 3-44-9.gif

47. Patient Counseling Tip  Macrolides interact with many other medications. Review the patient’s full medication list before use— particularly if the patient is using drugs that affect heart rate 47

48. 48

49. Tetracyclines  Originally isolated from the Streptomyces genus of bacteria  Have a broad antimicrobial spectrum  Commonly used in acne, UTI, and atypical infections 49

50. Tetracycline Structure 50 http://upload.wikimedia.org/wikipedia/commons/8/84/Tetracyclines.png

51. Tetracycline Mechanism of Action  Bind to the 30s ribosomal subunit in susceptible bacteria Distinguish from macrolides, which bind to the 50s subunit  Specifically block the A-site so that the incoming aminoacyl-tRNA cannot bind Distinguish from macrolides, which block the P- site  This stops the addition of new amino acids to the growing protein chain—inability to synthesize new proteins results in bacterial death 51

52. Tetracycline Mechanism of Action 52

53. Tetracyclines  Tetracycline (naturally occuring)  Demeclocycline (naturally occuring)  Doxycycline  Minocycline  Tigecycline* 53

54. Patient Counseling Tip  Do not take tetracyclines with dairy products, multivitamins, or antacids Take 2 hours before or 4 hours after 54

55. 55

56. Fluoroquinolones  Fully synthetic, broad range antibiotics  Widely used as eye/ear drops, as well as oral and IV formulation 56

57. Fluoroquinolone Structure 57 http://upload.wikimedia.org/wikipedia/commons/thumb/1/17/Quino lone.svg/500px-Quinolone.svg.png

58. Fluoroquinolone Mechanism of Action  Bind to and inhibit DNA gyrase in gram negative bacteria and Topoisomerase in gram positive bacteria  These enzymes aid in the process of unwinding/rewinding DNA during replication  Inhibiting their action disrupts DNA replication, causing cell death 58

59. Fluoroquinolone Mechanism of Action 59 http://www.seminfect.be/D-Low-28-06-01/img039.gif

60. Fluoroquinolones  Ciprofloxacin  Ofloxacin  Levofloxacin  Moxifloxacin  Gatifloxacin  Gemifloxacin 60

61. Patient Counseling Tip  Do not take fluoroquinolones with dairy products, multivitamins, or antacids Take 2 hours before or 4 hours after 61

62. 62

63. Metronidazole  Used in the treatment only of ANAEROBIC bacterial infections  Also used to treat infections from protozoa and amoebas 63

64. Metronidazole Structure 64 http://upload.wikimedia.org/wikipedia/commons/thumb/f/f1/Metronidazole.svg/500px -Metronidazole.svg.png

65. Metronidazole Mechanism of Action  Metronidazole is taken into the bacterial cell and reduced by ferredoxin  The reduced form of metronidazole is a toxic free-radical  This free-radical covalently binds to and deactivates many bacterial enzymes-- disrupting vital functions 65

66. Patient Counseling Tip  Do not consume any alcohol during course of therapy or for 3 days afterwards 66

67. Antimicrobial Overview 67

68. 68

69. Antibiotic Resistance  Bacteria grow and divide very rapidly, and as a result have quickly developed resistance to many antibiotics  Regardless of the antibiotic or bacteria, resistance to antibiotics occurs through five main mechanisms 69

70. Antibiotic Resistance  Drug inactivation/modification  Altered target site  Altered metabolic pathway  Decrease drug permeability  Efflux pump 70

71. Pharmacist’s Role  Help ensure proper use, selection, and duration of antibiotics  Counsel patients on potential side effects and drug interactions with antibiotic use  Counsel patients on importance of taking ALL of their antibiotic regimen  Others? 71

72. References 1. Petri WA. Chapter 52. Sulfonamides, Trimethoprim-Sulfamethoxazole, Quinolones, and Agents for Urinary Tract Infections. In: Chabner BA, Brunton LL, Knollman BC, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 12nd ed. New York: McGraw-Hill; 2011. http://www.accesspharmacy.com/content.aspx?aID=16677067. Accessed June 28 2012 http://www.accesspharmacy.com/content.aspx?aID=16677067 2. Petri WA. Chapter 53. Penicillins, Cephalosporins, and other beta-lactam antibiotics. In: Chabner BA, Brunton LL, Knollman BC, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 12nd ed. New York: McGraw-Hill; 2011. http://www.accesspharmacy.com/content.aspx?aID=16677067. Accessed June 28 2012 http://www.accesspharmacy.com/content.aspx?aID=16677067 3. Petri WA. Chapter 55. Protein Synthesis Inhibitors and Miscellaneous Antimicrobial agents. In: Chabner BA, Brunton LL, Knollman BC, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 12nd ed. New York: McGraw-Hill; 2011. http://www.accesspharmacy.com/content.aspx?aID=16677067. Accessed June 28 2012 http://www.accesspharmacy.com/content.aspx?aID=16677067 72

73. Questions 73

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