ANTIBACTERIAL DRUGS.pptx a comprehensive

For learning purposes

1. ANTIBACTERIAL DRUGS Eden MEDICAL UNIVERSITY

2. LEARNING OBJECTIVES At the end of this lecture each student should be able to: 1. Describe the difference between gram + ve and gram – ve bacteria. 2. State the different classes of antibacterial drugs. 3. Describe the mechanism of drug action, indications and adverse effects of Antibacterial drugs. 2 3/22/2023

3. Gram+ vs. Gram- Cell Walls Gram + ve cells have a very thick , peptidoglycan. Gram - ve cells have a very thin layer of peptidoglycan plus a thin outer layer. Have an outer (Lipid) membrane in addition to the cytoplasmic membrane, the space between these two membranes is called the periplasmic space or periplasm Clinical importance. Gram + ve bacteria have highly porous membrane allowing large molecular weight and charged antibiotics to pass through and reach the binding sites. Highly charged or large molecular weight antibiotics cannot cross the outer (lipid) membrane of the gram - ve bacteria to reach the binding sites in the inner cytoplasmic membrane 3

4. Gram positive Bacteria 3/22/2023 4

5. Gram negative Bacteria 3/22/2023 5

6. Classification Based on MoA 6 3/22/2023

7. INHIBITORS OF BACTERIAL CELL WALL SYNTHESIS Cell wall active agents; Beta Lactams : Penicillins , Cephalosporins , Carbapenems , Aztreonam . Polypeptides: Daptomycin Glycopeptides: Vancomycin and Teicoplanin. . 7 3/22/2023

8. Penicillins  Basic Structure Thiazolidone ring is attached to a β-lactam ring.       Contains one alterable side chain (R group), which can confer different antibacterial and pharmacological properties.   3/22/2023 . 8

9. Mechanism of action Penicillins inhibit bacterial cell wall synthesis by interfering with transpeptidation . They bind to transpeptidase and act as competitive inhibitors leading to synthesis of a defective cell membrane, which is osmotically less stable. Penicillins are bactericidal (kill bacteria) 3/22/2023 . 9

10. Classification Classified as narrow or broad spectrum. Classification Narrow Spectrum Wide Spectrum Anti Pseudomonal: Piperacillin Ticarcillin Carbecilin Azlocilin Mezlocilin Extended Spectrum: Amoxicillin Ampicillin 10 Very Narrow: Meficillin Nafcilin Cloxacillin Dicloxacillin Flucloxacillin Oxacillin Natural Penicillins : Pen V Pen G 3/22/2023

11. Natural Penicillins/Narrow spectrum Moderately narrow spectrum: BENZYL PENICILLIN (PENICILLIN G) Streptococcus species, meningococcus, clostridium tetanus, clostridium welchii , gonococcus, treponema pallidum and many other spirochetes. Inactivated by gastric acid therefore given IV or IM PHENOXYMETHYL PENICILLIN (PENICILLIN V) Stable to gastric acid therefore given orally less active than penicillin G Penicillin G and Penicillin V are inactivated by beta lactamases   3/22/2023 . 11

12. Penicillins resistant to beta-lactamases Very narrow spectrum Also called anti staphylococcal Penicillins Examples: Methicillin, Nafcilllin , Cloxacillin , Dicloxacillin , Flucloxacillin , Oxacillin Used for treatment of beta lactamase producing staphylococci infections 3/22/2023 L. 12

13. Broad spectrum Penicillins (Amino Peni ..) Members include: Ampicillin and Amoxicillin . Have more activity against gram - ve organisms than natural penicillins. Easily inactivated by beta lactamases. Ampicillin and Amoxicillin can be protected from destruction by beta-lactamases if they are co-administered with beta lactamase inhibitors e.g. Amoxicillin + Clavulanic acid and Ampicillin + Sulbactam 3/22/2023 L. 13

14. Anti pseudomonal Members include, Piperacillin, Ticarcillin . These can be protected from destruction by beta-lactamases if they are co-administered with beta lactamase inhibitors e.g. Piperacillin + Tazobactam , and Ticarcillin + Clavulanic acid. These have activities against pseudomonas. 14 3/22/2023

15. Adverse effects Hypersensitivity reactions Neurotoxicity with high doses Nausea, diarrhea. 3/22/2023 15

16. Cephalosporins Basic Structure   Similar to penicillin, they are β - lactam antibiotics 3/22/2023 L. 16

17. Mechanism of action Similar to penicillins : Binding to specific penicillin binding proteins (PBPs) that serve as drug receptors on bacteria Inhibition of cell wall synthesis by blocking transpeptidation of peptidoglycan Activation of autolytic enzymes in the cell wall, which result in bacterial death   3/22/2023 17

18. Classification of Cephalosporins Have been divided into the five major groups (generations) depending mainly on the spectrum of anti-microbial activity Broader spectrum of antibacterial activities More stable/resistant to β -lactamase hydrolysis 3/22/2023 18

19. First-Generation Cephalosporins 1 st Generation: Cephalexine , cefadroxil , cefazolin , cephaprin , cephalotin , caphadrin . Active against G + ve and some G - ve Uses: URTI, LRTI, UTI   3/22/2023 19

20. Second-Generation Cephalosporins 2 nd Generation: Cefuroxime cefoxitin, cefamandole, cefprozil Have extended activity against GNB while retaining activity against G + ve orgs; Uses: community acquired pneumonia, URTI and UTI.   3/22/2023 20

21. Third-Generation Cephalosporins 3 rd Generation: Cefotaxime, ceftriazone , ceftazidime, cefpodoxime, cefixime Extended G- activities but less G+ effects Uses: G- infections, pseudomonal infections, G- meningitis, gonorrhea, UTI, osteomyelitis 3/22/2023 L. 21

22. Fourth-Generation Cephalosporins 4 th Generation : Cefepime More resistant by β -lactamases to hydrolysis Good activity against Pseudomonas, enterobacteria , as well as Staph, Strept , haemophilus , and Neisseria Uses: Infections caused by above organisms L. 22 3/22/2023

23. Adverse effects of Cephalosporins Local irritation after intramuscular injection Thrombophlebitis after intravenous injection Pseudomembranous colitis. Allergic reactions: Similar to penicillin Interstitial nephritis Renal tubular necrosis Bleeding disorders 3/22/2023 . 23

24. Other Beta-lactam drugs Monobactams Example: Aztreonam Resistant to beta-lactamases and active against gram-negative rods (including pseudomonas & serratia ) Have no activity against gram-positive bacteria or anaerobes 3/22/2023 24

25. Carbapenems Examples: Imipenem , Meropenem . Have very broad spectrum of antimicrobial activity. Active against many aerobic & anaerobic gram-positive and gram-negative organisms. Pseudomonas rapidly develops resistance. 3/22/2023 25

26. Glycopeptide : Vancomycin Vancomycin is active only against gram-positive microorganisms. Acts by inhibiting cell wall synthesis. Inhibits biosynthesis of peptidoglycan Peptidoglycan: Major structural component of bacterial cell wall 3/22/2023 . 26

27. Clinical uses Used mainly against G(+) organisms e.g. Staph. epidermis, S.pyogenes , S.pneumonia Used to treat E. faecalis in combination with aminoglycosides in patients allergic to penicillin No significant oral absorption, so given IV Drug of choice for treating clostridium difficile colitis via oral administration 3/22/2023 . 27

28. Adverse effects Nephrotoxicity Pain and thrombophlebitis with IV route Ototoxicity Occasional mild hematuria, proteinuria, azotemia, casts in urine –Hypotensive reaction associated with rapid IV administration –Hypersensitivity 3/22/2023 28

29. Polypeptides e.g Daptomycin Activity similar to vancomycin Alters membrane potential resulting in K+ leakage and cell death by creating artificial pores on membrane Cleared by the kidneys Uses: once daily dosing for skin infections, bacteraemia , endocarditis. A/E: Myopathy 3/22/2023 29

30. PROTEIN SYNTHESIS INHIBITORS Bacteriostatic Agents : Bind to and interfere with bacterial ribosomal function Tetracylines , Chloramphenicol, Macrolides, Clindamycin Aminoglycosides, Spectinomycin 3/22/2023 L. 30

31. Protein Synthesis Inhibitors 50S ribosome inhibitors -Macrolides -chloramphenicol 30S ribosome inhibitors -Aminoglycosides -Tetracyclines 3/22/2023 . 31

32. Tetracycline Specific drugs Doxycycline Minocycline Tetracycline 3/22/2023 . 32

33. Activity: Broad spectrum & Bacteriostatic Many G + and G – orgs, rickettsia, mycoplasma, and chlamydia Bacteria concentrate antibiotic internally 3/22/2023 . 33

34. Classification Short acting tetracyclines Tetracycline, oxytetracycline T ½ 6-8 hrs Long acting tetracyclines Doxycycline, minocycline, T ½ 16-18 hrs Tigecycline : t ½ 36 hrs 3/22/2023 . 34

35. Clinical Uses of Tetracyclines Treatment of infections caused by Rickettsia, Mycoplasma, Chlamydia Spirochetes Gram + and gram - organisms 3/22/2023 . 35

36. Side effects/ Adverse drug reactions Tooth enamel dysplasia and possible reduction in bone growth in children.(avoid) Impaired liver function during pregnancy.(avoid) Sensitivity to light (photosensitivity) – doxycycline Superinfection leading to candidiasis or colitis 3/22/2023 L. 36

37. Aminoglycosides They are bactericidal drugs Examples include; Streptomycin, Kanamycin, Gentamicin, Tobramycin, Amikacin , and Neomycin (topical) 3/22/2023 37

38. Mode of action They act by blocking bacterial protein synthesis by binding to the 30S ribobosomal subunit 3/22/2023 38

39. Antimicrobial activity . Many gram-negative and some gram-positive bacteria. Synergy - The aminoglycosides synergize with beta-lactam antibiotics. The beta lactams inhibit cell wall synthesis and thereby increase the permeability of the aminoglycosides 3/22/2023 . 39

40. Clinical Uses Treatment of infections caused by susceptible organisms With penicillins to treat enterococcal endocarditis Treatment of meningitis Topical preparations for burns, wounds, eye infections, etc 3/22/2023 L. 40

41. Adverse Effects Nephrotoxicity (Neomycin, Kanamicin , Amikacin) Ototoxicity; Induces deafness (Neomycin, Tobramycin, Gentamycin) 3/22/2023 L. 41

42. Macrolides Macrolide antibiotics have an antibacterial spectrum similar but not identical to that of penicillin. Examples Erythromycin Azithromycin Clarithromycin 3/22/2023 42

43. Mechanism of action Macrolides bind to bacterial 50S ribosomes and inhibit protein synthesis. Produce bacteriostatic. 3/22/2023 . 43

44. Activity Broad spectrum of antimicrobial activity against; Gram positive cocci Atypical organism (mycoplasma, chlamydia Legionella pneumophilia H.pylori - treatment of ulcers due to h.pylori Treponema Mycobacteriam avium 3/22/2023 . 44

45. Clinical Uses Useful for treatment of: Community acquired pneumonia Staphylococcal infections Chlamydial infection: eyes, respiratory tract, genitals 3/22/2023 L. 45

46. Chloramphenicol Broad spectrum antimicrobial and penetrates tissue very well. It is bacteriostatic but is extremely effective against streptococci and staphylococi . It is curently a backup drug for infections due to salmonella typhi , rickettsia and possibly in bacterial meningitis MoA Inhibits 50S ribosomal subunit of bacteria Specifically inhibits peptide bond formation 3/22/2023 . 46

47. Clinical Uses & ADR Bacterial meningitis Eye and ear infections Typhoid fever Nausea, vomiting and diarrhea Predispose to Candida infections (oral and vaginal) Dose related myelosuppression Aplastic anemia 3/22/2023 . 47

48. TOPOISOMERASE INHIBITORS; Quinolones Inhibition of topoisomerases II(DNA gyrase) and prevents replication or transcription of DNA. 3/22/2023 48

49. Quinolones cont ’ Nalidixic acid, Norfloxacin – active against G- orgs Ciprofloxacin, Levofloxacin, Ofloxacin – active against G- and G+ Moxifloxacin – better G+. 3/22/2023 L. 49

50. Quinolones: Therapeutic Uses Lower respiratory tract infections Bone and joint infections Infectious diarrhea Urinary tract infections Skin infections Sexually transmitted diseases TB treatment 3/22/2023 . 50

51. Adverse Effects Well tolerated GIT related ECG abnormalities Destruction of cartilage in growing children – arthropathy Tendonitis (adults) Avoid in pregnancy 3/22/2023 51

52. END. THANK YOU Any questions? 52 . 3/22/2023

53. FURTHER READING Rang H. P, Dale M. M, Ritter J. M, Flower R. J, Henderson G. Rang & Dale’s Pharmacology, 7 th ed. Ch.50. Churchill-Livingstone Katzung B. G. Basic & Clinical Pharmacology,12 th ed. Ch. 43–46. McGraw-Hill. 3/22/2023 53