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Cephalosporins & other β lactam  antibiotics Slide 1 Cephalosporins & other β lactam  antibiotics Slide 2 Cephalosporins & other β lactam  antibiotics Slide 3 Cephalosporins & other β lactam  antibiotics Slide 4 Cephalosporins & other β lactam  antibiotics Slide 5 Cephalosporins & other β lactam  antibiotics Slide 6 Cephalosporins & other β lactam  antibiotics Slide 7 Cephalosporins & other β lactam  antibiotics Slide 8 Cephalosporins & other β lactam  antibiotics Slide 9 Cephalosporins & other β lactam  antibiotics Slide 10 Cephalosporins & other β lactam  antibiotics Slide 11 Cephalosporins & other β lactam  antibiotics Slide 12 Cephalosporins & other β lactam  antibiotics Slide 13 Cephalosporins & other β lactam  antibiotics Slide 14 Cephalosporins & other β lactam  antibiotics Slide 15 Cephalosporins & other β lactam  antibiotics Slide 16 Cephalosporins & other β lactam  antibiotics Slide 17 Cephalosporins & other β lactam  antibiotics Slide 18 Cephalosporins & other β lactam  antibiotics Slide 19 Cephalosporins & other β lactam  antibiotics Slide 20 Cephalosporins & other β lactam  antibiotics Slide 21 Cephalosporins & other β lactam  antibiotics Slide 22 Cephalosporins & other β lactam  antibiotics Slide 23 Cephalosporins & other β lactam  antibiotics Slide 24 Cephalosporins & other β lactam  antibiotics Slide 25 Cephalosporins & other β lactam  antibiotics Slide 26 Cephalosporins & other β lactam  antibiotics Slide 27 Cephalosporins & other β lactam  antibiotics Slide 28 Cephalosporins & other β lactam  antibiotics Slide 29 Cephalosporins & other β lactam  antibiotics Slide 30 Cephalosporins & other β lactam  antibiotics Slide 31 Cephalosporins & other β lactam  antibiotics Slide 32 Cephalosporins & other β lactam  antibiotics Slide 33 Cephalosporins & other β lactam  antibiotics Slide 34 Cephalosporins & other β lactam  antibiotics Slide 35 Cephalosporins & other β lactam  antibiotics Slide 36 Cephalosporins & other β lactam  antibiotics Slide 37 Cephalosporins & other β lactam  antibiotics Slide 38 Cephalosporins & other β lactam  antibiotics Slide 39 Cephalosporins & other β lactam  antibiotics Slide 40 Cephalosporins & other β lactam  antibiotics Slide 41 Cephalosporins & other β lactam  antibiotics Slide 42 Cephalosporins & other β lactam  antibiotics Slide 43 Cephalosporins & other β lactam  antibiotics Slide 44 Cephalosporins & other β lactam  antibiotics Slide 45 Cephalosporins & other β lactam  antibiotics Slide 46 Cephalosporins & other β lactam  antibiotics Slide 47 Cephalosporins & other β lactam  antibiotics Slide 48 Cephalosporins & other β lactam  antibiotics Slide 49 Cephalosporins & other β lactam  antibiotics Slide 50 Cephalosporins & other β lactam  antibiotics Slide 51 Cephalosporins & other β lactam  antibiotics Slide 52 Cephalosporins & other β lactam  antibiotics Slide 53 Cephalosporins & other β lactam  antibiotics Slide 54
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Cephalosporins & other β lactam antibiotics

  1. 1. Cephalosporins & other β- Lactam Antibiotics.
  2. 2. β- Lactam Antibiotics β-lactam antibiotics, inhibit bacterial growth by interfering with bacterial cell wall synthesis. The β-lactam antibiotics may be further sub- divided into two categories: Penicillin Cephalosporin
  3. 3. Cephalosporins Cephalosporins are similar to Penicillins, but more stable to bacterial β lactamases and therefore have a broader spectrum of activity.
  4. 4. History The 1st source of Cephalosporins, Cephalosporium acremonium(Fungus), was isolated in 1948 by Giuseppe from the sea near a sewer outlet of the Sardinian Coast. The crude filtrates from this fungus were found to inhibit the in vitro growth of β- lactamase producing S. aureus and to cure the Staphylococcal infections and typhoid fever in humans.
  5. 5. Subsequently, Abraham and his colleagues identified three distinct antibiotics from the culture fluid of fungus. These antibiotics were named Cephalosporin N and C (which were chemically related to penicillin) and Cephalosporin P, a steroid antibiotic that resembles Fusidic Acid.
  6. 6. Chemistry The nucleus of Cephalosporins, 7- aminocephalosporanic acid bears a close resemblance to 6-aminopencillanic acid. The core of the basic cephalosporin molecule consists of a two ring system which includes a β-lactam ring condensed with dihydrothiazine ring. The core itself can also be referred to as 7- aminocephalosporanic acid which can be derived by hydrolysis from the natural compound Cephalosporin C.
  7. 7. Chemical compounds containing this core are relatively stable to acid hydrolysis and tolerance to β- lactamases. Cephalosporin C ring structure contains a side-chain.
  8. 8. Modification of side chains on the relevant positions has been used to create a whole new class of cephalosporin antibiotics. Modification of side-chains at position 7 of the lactam ring seems to affect the antibacterial activity while position 3 of the dihydrothiazine ring alters pharmacokinetic properties and receptor binding affinity.
  9. 9. Mechanism of Action Cephalosporins exert bactericidal effect in manner similar to that of Penicillins. Binding to specific PBPs Inhibition of cell wall synthesis by inhibiting transpeptidation of Peptidoglycan Activation of Autolytic enzymes Autolysins or Murein Hydrolases
  10. 10. Classification Cephalosporins can be classified into four major groups or generations, depending mainly on the spectrum of antimicrobial activity. Recently, Fifth generation cephalosporins were developed in the lab to specifically target against resistant strains of bacteria particularly Methicillin Resistance Staphlococcus Aureus (MRSA).
  11. 11. 1st Generation Cephalosporins The agents included in this group have good activity against gram-positive cocci, such as pneumococci, streptococci and staphylococci but not active against methicillin resistant strains of staphylococci, and relatively modest activity against gram-negative microorganisms (E.Coli and Klebsiella pnumoniae).
  12. 12. 1st generation Cephalosporins include: Cefazolin (IV/IM) Cefadroxil (PO) Cephalexin (PO) Cephalothin (IV/IM) Cephapirin (IV/IM) Cephradine (PO)
  13. 13. 2nd Generation Cephalosporins These compounds show modest activity against gram-positive bacteria (less active than 1st generation drugs) and display greater activity against gram-negative microorganisms including Haemophilus influenza, some Enterobacter and Neisseria Species.
  14. 14. In comparison to 1st generation, they have some what increased activity against gram- negative bacteria but this activity is much less than the activity of 3rd generation compounds.
  15. 15. The drugs included in this class are: Cefaclor (PO) Cefamandole (IV/IM) Cefonicid (IM/IV) Cefuroxime (IV/IM/PO) Cefprozil (PO) Loracarbef (PO) Ceforanide (IM/IV)
  16. 16. 3rd Generation Cephalosporins Though greatly inferior to 1st generation cephalosporins in regard to their activity against gram-positive cocci, the 3rd generation cephalosporins exhibit much more activity against gram-negative bacilli, most other enteric organisms and β- lactamase producing strains of Haemophilus and Neisseria.
  17. 17. Drugs of this group have superiority over the other two generation in having ability to reach CNS (cross BBB). They include: Cefoperazone (IV/IM) Cefotaxime (IV/IM) Ceftriaxone (IV/IM) Cefixime (PO) Ceftazidime (IV/IM) Moxalactam (IM/IV)
  18. 18. 4th Generation Cephalosporins They have an extended spectrum of activity as compared to the 3rd generation and have increased stability from hydrolysis by β- lactamases.
  19. 19. Aerobic gram-negative bacilli resistant to 3rd generation cephalosporins can be successfully treated with 4th generation drugs. Drugs included in this class are: Cefepime (IV) Cefpirome (IV) Cefozopran (IV)
  20. 20. 5th Generation Cephalosporins These 5th generation cephalosporins are active against Methicillin resistant staphylococci. Agents under this class include: Ceftaroline Fosamil (IV) Ceftobiprole (IV)  Ceftolozane
  21. 21. FDA has approved Ceftaroline under the trade name Teflaro which was developed by modifying the structure of 4th generation cephalosporin Cefozopran. Ceftobiprole has powerful antipseudomonal characteristics and appears to be less susceptible to development of resistance and are now on the FDA fast-track.
  22. 22. Currently, ceftaroline and ceftobiprole are on an unnamed subclass of cephalosporins by the Clinical and Laboratory Standards Institute (CLSI) but generally classified under the category of 5th generation cephalosporins.
  23. 23. Others  Cefaloram  Cefaparole  Cefcanel  Cefedrolor  Cefmatilen  Cefmepidium  Cefrotil  Cefsumide  Nitrocefin
  24. 24. Nitrocefin isa chromogenic cephalosporin substrate routinely used to detect the presence of beta-lactamase enzymes produced by various microbes. As a cephalosporin, nitrocefin contains a beta- lactam ring which is susceptible to beta lactamase mediated hydrolysis. Once hydrolyzed, the degraded nitrocefin compound rapidly changes color from yellow to red. Although nitrocefin is considered a cephalosporin, it does not appear to have antimicrobial properties.
  25. 25. Resistance to Cephalosporins Resistance to cephalosporins can be due to following mechanisms: Poor penetration of drug into bacteria Lack of specific PBPS for a particular agent Degradation of the drug by β-lactamases Failure of activation of Autolytic enzymes in the bacterial cell wall.
  26. 26. Therapeutic Uses Cephalosporins are widely used antibiotics. Unfortunately, overuse of these agents in situations where drugs with less broad spectrum activity would be more appropriate has led to the emergence of wide array of cephalosporin resistant bacteria. Cephalosporins are effective as both Prophylactically & Therapeutically.
  27. 27. Chemoprophylaxis Single dose of Cefazoline (1-2 g IV/IM ≤60 minutes before procedure) just before surgery is preferred prophylaxis for procedures in which skin flora are likely to be pathogenic.
  28. 28. Alternative to Penicillins Cephalosporins are still useful alternatives to Penicillins for a variety of infections in patients who cannot tolerate penicillins.
  29. 29. Infections Cefotaxime and ceftriaxone are approved for use in essentially all pediatric bacterial infections, including sepsis, meningitis, pneumonia, those of the skin and soft tissues, septic arthritis, osteomyelitis, intra- abdominal, and infections of the genitourinary tract.
  30. 30. Ceftazidime is the most active third- generation cephalosporin against P aeruginosa. It exhibits excellent penetration to the CSF and is effective in the treatment of meningitis caused by P aeruginosa. Ceftazidime commonly is combined with an aminoglycoside for the treatment of acute exacerbations of bronchopulmonary infections in patients who have cystic fibrosis.
  31. 31. Ceftolozane is combined with the β- lactamase inhibitor tazobactam, as multi- drug resistant bacterial infections will generally show resistance to all β-lactam antibiotics unless this enzyme is inhibited.
  32. 32. Treatment of Gonorrhoea Ceftriaxone (as a single dose 125mg by injection) and Cefixime (400mg oral dose) are drugs of 1st choice for the treatment of all forms of gonorrhoea.
  33. 33. Treatment of Typhoid Cefoperazone and Ceftriaxone (1-2g BD, IV/IM for 7-10 days) have been used effectively for the treatment of typhoid fever.
  34. 34. Meningitis Ceftriaxone and Cefotaxime, currently are the drug of choice for empirical treatment of meningitis in non immunocompromised adults and children older than 3 months. They are proven effective for the treatment of meningitis caused by Haemophilus influenzae, Neisseria meningitidis.
  35. 35. Treatment of Lyme Disease Lyme is an inflammatory disease spread by infected Tics bite by Borrelia specie. Ceftriaxone (2 g once daily iv for 14–28 days) or Cefotaxime (2 g iv every 8 h) is the treatment of choice for severe forms of Late Lyme Disease.
  36. 36. Adverse Effects Allergic Reactions (Rare) Nephrotoxicity Diarrhoea (cefixime, cefoperazone) Disulfiram like Reaction (cefoperazone and cefamandole) Hypoprothrobinemia (common with cefoperazone and cefamandole) Phlebitis, pain on IM Injection (cefotaxime, cefalothin)
  37. 37. Other β-Lactam Antibiotics & Cell Wall Destructor
  38. 38. Other β-Lactam Antibiotics β-Lactamase Inhibitors Clavulanic Acid Salbactum Tazobactum Monobactams Aztreonam
  39. 39. Carbapenems Doripenem Imipenem Ertapenem Meropenem
  40. 40. β-Lactamase Inhibitors β-lactamase inhibitors are used in conjunction with a β-Lactam antibiotic to extend its spectrum of activity. Although β-lactamase inhibitors have little antibiotic activity of their own, they instead inhibit the activity of β-lactamases, (a family of enzymes that break the beta- lactam ring) that allows penicillin-like antibiotics to work, thereby conferring bacterial resistance.
  41. 41. Hence β-lactamase inhibitors are often given in combination with penicillins to tackle the problem of the resistance caused by the presence of β-lactamases from bacterial cells. An example is Co-Amoxiclav [Augmentin], which is a combination of amoxicillin and clavulanic acid. Salbactum usually combined with Ampicillin (Unasyn) and Tazobactum with Piperacillin (Zosyn).
  42. 42. Monobactams Monobactams are drugs with a monocyclic β- lactam ring. They are resistant to β-lactamases and active against gram-negative rods. They have no activity against gram-positive bacteria or anaerobes. Penicillin-allergic patients tolerate aztreonam without reaction.
  43. 43. Carbapenems Imipenem has good activity against gram- negative, gram-positive and anaerobic organisms. Imipenem is inactivated by dehydropeptidases in renal tubules. It is administered with an inhibitor of renal dehydropeptidase, cilastatin, for clinical use. Meropenem and ertapenem are not degraded by renal dehydropeptidase.
  44. 44. Cell Wall Destructor Vancomycin Fosfomycin Polymyxin Cycloserine
  45. 45. Vancomycin Vancomycin is active against gram-positive bacteria, particularly staphylococci. Machanism: Inhibits cell wall synthesis by binding to the D-Ala-D-Ala terminus of peptidoglycan pentapeptide, preventing peptidoglycan elongation and cross-linking.
  46. 46. β-lactamase producing staphylococci and those resistant to nafcillin and methicillin are killed by vancomycin. Vancomycin is poorly absorbed from the GI tract.
  47. 47. It is used orally only for antibiotic- associated enterocolitis caused by C. difficile. Metronidazole is preferred as initial therapy and vancomycin is reserved for refractory cases. Parenteral vancomycin is used in sepsis caused by methicillin-resistant staphylococci.
  48. 48. Vancomycin is irritating to tissue, resulting in phlebitis at the site of injection.  A common reaction is "red man" or "red neck" syndrome (infusion related flushing). It can be largely prevented by prolonging the infusion period to 1-2 hours or increasing the dosing interval.
  49. 49. Fosfomycin It inhibits bacterial cell wall biogenesis by inactivating the cytoplasmic enzyme, enolpyruvate transferase. Fosfomycin is active against both gram- positive and gram-negative organisms. Fosfomycin is used for treatment of uncomplicated urinary tract infections.
  50. 50. Polymyxins Polymyxins antibiotic primarily used for resistant Gram-negative infections. Alters bacterial outer membrane permeability by binding to a lipopolysaccharide layer resulting in disruption of membrane integrity.
  51. 51. Polymyxin is applied topically to treat infections such as those of the eye, ear, and skin. Because polymyxins also react with the membranes of human cells, they can cause kidney damage and neurotoxicity. The availability of better antibiotics limits the use of polymixins.
  52. 52. Cycloserine Cycloserine is used only to treat tuberculosis resistant to first-line agents. Cycloserine causes serious CNS toxicity with headaches, tremors, acute psychosis, and convulsions.
  53. 53. Thanks
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Cephalosporins & other β lactam antibiotics

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