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β-lactam antibiotics

β-lactam antibiotics. 1928 – Fleming discovered penicillin, produced by Penicillium . 1940 – Howard Florey and Ernst Chain performed first clinical trials of penicillin. Penicillins. Figure 20.1. Sir Alexander Fleming. Penicillin. Derived from Penicillium notatum. Penicillins.

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β-lactam antibiotics

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  1. β-lactam antibiotics

  2. 1928 – Fleming discovered penicillin, produced by Penicillium. 1940 – Howard Florey and Ernst Chain performed first clinical trials of penicillin. Penicillins Figure 20.1

  3. Sir Alexander Fleming

  4. Penicillin Derived from Penicillium notatum

  5. 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

  6. 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

  7. 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

  8. 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

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

  10. Classification ofPenicillins

  11. * β-lactamase inhibitor

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

  13. 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

  14. 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

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

  16. Hives caused by allergy to penicillin

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

  18. CEPHALOSPORINS

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

  20. 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

  21. 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

  22. 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

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

  24. 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

  25. 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

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

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

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

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

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

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