1. Antimicrobial drugs Farah Morad IUG Faculty Of Medicine 220061056

2. The ability to kill an invading microorganism without harming the cells of the host.. Why ? differences between microorganisms and human beings Relative, rather than absolute Concentration..carefully controlled More antibacterial than antiviral …Why ? Selective toxicity

3. Broad & narrow spectrum : 1- Broad spectrum both gram-positive and gram-negative the critically ill patient delay..example ?? tetracycline,chloramphenicol Superinfection

4. 2- Narrow spectrum: more specific.. Isoniazid for Mycobacteria..Name?, Penicillin 3- Extended spectrum: effective against gram-positive & significant Number of gram-negative bacteria Ampicillin

6. Bacteriostatic & Bactericidal ** Bacteriostatic (1) the bacteria can grow again (2) host defense mechanisms ** Bactericidal 1- Immediately life-threatening infection 2-leukocyte count is below 500/IuL 3-Endocarditis, phagocytosis is limited

7. Inhibition of bacterial Cell Wall Synthesis: III. Mechanisms of Antimicrobial Drugs

9. B-Iactam drugs: Penicillins and cephalosporins. Non B-Iactam drugs: Vancomycin,Cycloserine & Bacitracin

10. Inhibition of bacterial Cell Wall Synthesis: Penicillin 1-Transpeptidases (pbps) No cross-linking peptidoglycan 2- Autolytic enzymes : murein hydrolases Staphylococcus aureus, : Tolerant

11. Penicillins kill bacteria when they are growing which phase of bacterial Growth ? Log Phase Gram +ve or –ve ? Why ? Gram +ve because they have a cell wall Gram –ve have a cell membrane

12. Penicillin Mechanism of Action - Animation Shift +F5 to see the animation

13. penicillin Kills Bacteria in log phase

14. Disadvantages: 1-limited effectiveness against many gram-negative rods.. Why ? Extended-spectrum penicillins ampicillin & amoxicillin.. modified R Ampicillin 4 /daily Amoxicillin 3/ daily.. Compliance Pseudomorms aeruginosa,,No effect Because it Lacks porins 2-hydrolysis by gastric acids..oral effectiveness ?? oxygen : penicillin V amino group: ampicillin

16. (3) inactivation by B-lactamases. A -methicillin, oxacillin, nafcillin, large aromatic rings contain- bulky methyl or ethyl B-inhibitors such clavulanic acid and and supbactam. -(Augmentin) Combinations, amoxicillin and clavulanic acid.. Expensive !! (4) disadvantage hypersensitiv- anaphylaxis, in 0.5% of patients..fatal skin rashes, hemolytic anemia, nephritis, fever. No solution till now !

18. Bacterial Resistance to penicillin Beta lactamases Alteration of PBP (Pseudomonas) Penicilinase-resistant penicillins Augmentin,Naficillin, sublactam,Methacillin,Floxacillin Extended-spectrum penicillins ampicillin & amoxicillin Shift +F5 To see the animation

19. B- lactamases- Animation Shift +F5 to see the animation

20. Forms of penicillin G 1-Aqueous 2-Procaine..IM 3-Benzathine..depot

21. Cephalosporins - against gram-positive cocci primarly..1 st Generation - From 1- 4 generations : increased sensitivity to gram –ve -4 th against a broad range of organisms, -Same Action of penicilllin - fewer hypersensitivity reactions than do the penicillin

22. Carbapenems: (Imipenem) - B-lactam drugs - not inactivated by most B-Lactamases. - structurally different from penicillins and cephalosporins - widest spectrum of activity of the B-Lactam - many gram-positive, gram-negative, and anaerobic bacteria - In combination with cilastatin an inhibitor of dehydropeptidase a kidney enzyme that inactivates imipenem.

23. Monobactams (Aztreonam) - B-lactam - resistant to most B-lactamases…Good !! - they are monocyclic - Aztreonam, has excellent activity against many gram -ve rods - no cross-reactivity.. Patients hypersensitive to penicillin

24. Vancomycin: not B-lactam Transpeptidase compititive inhibition binds directly to the D-alanyl-D-alanine of peptidoglycan bactericidal against gram-positive bacteria Uses: 1-S. aureus strains resistant to the penicillinase-resistant penicillins (MRSA) VMRSA?!!! 2- Antimicrobial induced Cholitis …Oral

25. Vancomycin Action –Animation Shift +F5 to see the animation

26. Cycloserine 1- analogue of D-alanine inhibits dipeptide D-alanyl-D- alanine 2- It is used as a second line drug in the treatment TB Remember : What first line ?? Great !! Rifampin & isoniazide

27. Bacitracin 1- prevents dephosphorylation of the phospholipid carrier of the peptidoglycan 2- Treatment of superficial skin infections (Topical) too toxic for systemic use.

28. 2. Inhibition of Fungal Cell Wall Synthesis Caspofungin - lipopeptide -Inhibition of B-glucan synthase -Aspergillus and Candida but not Cryptococcus or Mucor. -Disseminated candidiasis and Invasive aspergillosis

29. Principle: - differences between bacterial and human ribosomal proteins, RNAs - Bacteria 70S..50S and 30S subunits, - human cells have 80S..60S and 40S subunits 3- INHIBITION OF PROTEIN SYNTHESIS

31. I. Drugs That Act on the 30S Subunit Aminoglycosides No Initiation complex.. and misreading (mRNA) Are bactericidal drugs.. Broad spectrum Streptomycin, neomycin, gentamycin,tobramycin,Kanamycin.

32. Aminoglycosides Animation-1 Shift +F5 to see the animation

33. Aminoglycosides Animation 2 Shift +F5 to see the animation

34. Aminoglycosides cont. 1- Toxicicity the kidneys How to Avoid ?? Urea & Creatinine tests 2- eighth cranial nerveToxicicity 3- Cannot be given orally. 4- Must be given intrathecally meningitis. 5- Ineffective against anaerobes..Needs O2 to enter cells

35. Tetracyclines Bacteriostatic Gram +ve & -ve bacteria, mycoplasmas, chlamydiae, and rickettsiae. The 30S ribosomal & (tRNA) Selectivity : greatly increased uptake into susceptible bacteria compared with human cells. Doxacycline…(Cholera)

36. Side Effects : 1- Diarrhea & superinfection. 2- Brown staining of the teeth of fetuses and young children 3- Tetracydines are avid calcium chelators 4- Contraindicated for use in pregnant women and in children<8

37. * Advantages of drug combinations show synergism - B-Iactams and aminoglycosides,. - B-lactams + calvulanic acid Disadvantages of drug combinations bacteriostasis & bactericidal.

38. Needs To modify drugs : 1- Change route of administration..Compliance 2- Overcome resistance 3- Minimize side effects 4-Wideninig Spectrum of activity

39. Thank you !