Penicillins and Cephalosporins: Mechanisms, Uses & Effects

1. β-lactam antibiotics

3. 1928 – Fleming discovered penicillin, produced by Penicillium. 1940 – Howard Florey and Ernst Chain performed first clinical trials of penicillin. Penicillins Figure 20.1

4. Sir Alexander Fleming

5. Penicillin Derived from Penicillium notatum

6. Penicillins • One of the most important and frequently used groups of antimicrobial agents • Naturally occurring & semi-synthetic antibiotics • Formulated in the form of tablets, capsules, suspensions & reconstituted powders • Have a common nucleus, 6-amino penicillanic acid; formed by a 5-membered thiazolidine ring connected to a 4-memebered β-lactam ring

8. Penicillins • Cleavage of β-lactam ring destroys the anti-bacterial activity • Bacterial β-lactamase (penicillinase) enzyme degrades the β-lactam ring • Cleavage of amide bond side-chain by amidase yields the 6-APA nucleus

11. Mechanism of action • Bind to a family of proteins called penicillin binding proteins (PBPS) • PBPS are involved in the maintenance of normal cell morphology, cell elongation & cell division • Blockade of cell wall synthesis • Activation of autolysins • Degradation of abnormally formed peptidoglycan

12. Gram positive bacteria are more susceptible to Penicillins • Most active during the log phase of bacterial growth • Less effective against formed bacterial cell wall • Time dependent antibacterial action

13. Bacterial resistance • β-lactamase/penicillinase producing bacteria • Quiescent/dormant bacteria • Bacteria with alteredPBPS

14. Classification ofPenicillins

17. * β-lactamase inhibitor

18. Routes of administration • Oral • Parentral • Topical • Intra-ocular • Intra-aural • Intra-mammary

19. Pharmacokinetics • Do not penetrate into the brain, bones, cartilages, cornea and CSF unless these sites are inflammed • Do not undergo significant biotransformation • Renal tubular excretion can be deliberately inhibited by Probenicid

20. Clinical uses • Penicillin G: • combined with Streptomycin • Prophylactically used before surgical operations, endoscopy & catheterization • Cloxacillin: • ocular infections • Staphylococcus-induced bovine mastitis • Co-amoxyclav: • Most frequently used Penicillin preparation

21. Adverse effects • Hypersensitivity reaction: • Characterized by rashes, urticaria, angio-neurotic edema • Cross-hypersensitivity • Cation toxicity: • Sodium excess may aggravate the CHF • Neurotoxicity • Dysbiosis & superinfection

22. Hives caused by allergy to penicillin

23. Drug interactions • Penicillins and aminoglycosides • Penicillins and bacteriostatic drugs • Penicillins and Probenecid • Acid-labile Penicillins and normal saline

24. CEPHALOSPORINS

25. Origin Semi-synthetically prepared from Cephalosporin-C, derived from a fungus Cephalosporium acremonium Initially isolated by Brotzu in 1948

28. Chemical features • Fusion of a dihydrothiazine ring with a β-lactam ring to form 7-aminocephalosporanic acid • Their physical and chemical properties resemble those of Penicillins • More water soluble and acid-stable than Penicillins

29. Mechanism of action • Inhibit the bacterial cell wall synthesis in a manner similar to that of Penicillins • Bind to different proteins than those required by Penicillins • Exert bactericidal action

31. Pharmacokinetics • Widely distributed in body tissues and fluids • Lungs, kidneys, bones, soft tissues • pleural, pericardial and synovial fluids • Capable to cross placental barrier • Some 3rd generation Cephalosporins also cross the blood brain barrier

32. Pharmacokinetics • Enter the milk in low concentrations • Undergo trivial biotransformation • Excreted unchanged in the urine • Probenicid increases the half-lives of Cephalosporins

33. Antimicrobial spectrum • 1st generation Cephaolsporins: Stronger activity against gram positive butweaker activity against gram negative bacteria • 2nd generationCephaolsporins: Greater activity against gram negative but somewhat lesser action against gram positive bacteria

34. Antimicrobial spectrum • 3rdgeneration Cephaolsporins: Most active against gram negative (especially enteric) bacteria but less active against gram positive cocci. • 4th generationCephaolsporins: Broad spectrum of activity covering gram positive cocci, gram negative bacilli and pseudomonas

35. Clinical uses • Large animal practice: • High cost • Limited use • Treatment of mastitis • Ceftiofur: • Bovine respiratory diseases (such as pneumonia & H. S) • UTIs (small animals)

36. Clinical uses • Cefotaxime: • Gram negative meningitis in small animals • Cefuroxime: • Meningitis caused by meningococci and pneumococci in human patients

37. Adverse effects Relatively non-toxic antibiotics • Hypersensitivity reactions: • Similar to that caused by Penicillins • Manifested by rashes, eosinophilia, lymphadenopathy and anaphylaxis • Cross-hypersensitivity

38. Adverse effects • Other un-wanted effects: • Potentially nephrotoxic drugs • Dysbiosis & superinfection

39. Bacterial resistance: • Acquisition of cephalosporinases • Alteration in target sites Drug interactions: • Concomitant use of other nephrotoxic drugssuch as Aminoglycosides & Loop diuretics • Bacteriostatic agents • Probenicid