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  2. 2. Introduction The cephalosporins are a class of β-lactam antibiotics originally derived from the fungus Acremonium, which was previously known as “Cephalosporium”.
  3. 3. Historical Background The aerobic mold which yielded cephalosporin C was found in the sea near a sewage outfall in SuSiccu, by Cagliari harbour in Sardinia (Italy), by the Italian pharmacologist Giuseppe Brotzu in 1945.Researchers at the Sir William Dunn School of Pathology at the University of Oxford isolated cephalosporin C, which had resistance to β-lactamases but was not sufficiently potent for clinical use. Cephalosporin compounds were first isolated from cultures of Acremonium strictum from a sewer in Sardinia in 1948 by Italian scientist Giuseppe Brotzu. He noticed these cultures produced substances that were effective against Salmonella typhi, the cause of typhoid fever, which had β-lactamase. Cephalosporins were first sold in 1964 (Cephalothin) by Eli Lilly.
  4. 4. 1945 - Cephalosporins were firstdetected in Cephalosporium acremonium 1948 - Cephalosporins are semisynthetic antibiotic derivatives ofcephalosporin C 1948 - Brotzu published his results in 1948 1964 - Alarmed by the need to keep ahead of rapidly mutating bacterialstrains, researchers since then have developed 4 generation cephalosporins. 1971 -In January 1971Eli Lilly introduced Keflex, generic name Cephalexin 1996 -In January 1996 a progressive reintroduction of cephalosporinsincluding the novel4th generation cephalosporincefepime
  5. 5. 2003-In February 2003 Ranbaxy laboratories has rolled out its high-endcephalosporin orcefprozilunder the brand name Refzil.Cephalosporins have an estimated Rs 1000-crore in India 2005 - Infact the risk that a patient with a history of penicillin allergywill experience a reaction to a first- generation cephalosporin notmore than 0.5%, second generation cephalosporin not more than 0.2% and a third-generation cephalosporin practicallynil in at least 25 studies 2010 -In October 2010 Ceftarolin (a fifth-generation cephalosporin) - was approved by the food and drug administration (FDA)
  6. 6. Cephalosporins are semisynthetic derivatives of Cephalosporin C. Cephalosporin C is an analogue of 7- aminocephalosporanic acid (7-ACA): Cephalosporin C
  7. 7. 7-Aminocephalosporanic acid (7-ACA)
  8. 8. Classification 1. First generation: First generation cephalosporins were the first cephalosporins on the market. They have good antimicrobial activity against gram-positive bacteria but limited activity against gram- negative species. Gram-positive: Activity against penicillinase-producing, methicillin-susceptible staphylococci and streptococci (though they are not the drugs of choice for such infections). No activity against methicillin- resistant staphylococci or enterococci. Gram-negative: Activity against Proteus mirabilis, some Escherichia coli, and Klebsiella pneumoniae, but have no activity against Bacteroides fragilis, Pseudomonas, Acinetobacter, Enterobacter, indole- positive Proteus, or Serratia.
  9. 9. Cephalothin (Cefalotin) Cephaloridine Cefalexin Cefradine Cefadroxil Cefatrizine Cefazolin
  10. 10. Cephalothin (Cefalotin) Cephaloridine Cefalexin Cefradine Cefadroxil
  11. 11. Cefatrizine Cefazolin
  12. 12. 2. Second generation: Early second generation cephalosporins are very similar in basic structure to the first generation. Gram-positive: Less than first-generation. Gram-negative: Greater than first-generation:Haemophilus influenzae, Enterobacter aerogenes and some Neisseria + Proteus mirabilis, some Escherichia coli, and Klebsiella pneumoniae. Cefaclor Cefprozil Cefamandole Cefuroxime Cephamycin C Cefoxitin Cefotetan Cefmetazole
  13. 13. Cefaclor Cefprozil Cefamandole Cefuroxime
  14. 14. Cephamycin C Cefoxitin Cefotetan Cefmetazole
  15. 15. 3. Third generation:The majority of third generation cephalosporins have the aminothiazole group at position C-7. Gram-positive: Some members of this group have decreased activity against gram-positive organisms.Activity against Staphylococci and Streptococci is less with the third-generation compounds than with the first- and second-generation compounds. Gram-negative: Third-generation cephalosporins have a broad spectrum of activity and further increased activity against gram-negative organisms. They are also able to penetrate the central nervous system, making them useful against meningitis caused by pneumococci, meningococci, H. influenzae, and susceptible E. coli, Klebsiella, and penicillin-resistant N. gonorrhoeae.
  16. 16. Cefotaxime Ceftriaxone Cefixime Cefoperazine Ceftibuten Ceftazidine
  17. 17. Cefotaxime Ceftriaxone
  18. 18. Cefixime Cefoperazine
  19. 19. Ceftibuten Ceftazidime
  20. 20. 4. Fourth generation:The fourth generation cephalosporins have greater activity against gram-negative bacteria than the second and third generation.This difference is attributed to them being dipolar ionic zwitterion compounds. Gram-positive: They are extended-spectrum agents with similar activity against Gram-positive organisms as first-generation cephalosporins. Gram-negative: Fourth-generation cephalosporins are zwitter-ions that can penetrate the outer membrane of Gram-negative bacteria. They also have a greater resistance to β-lactamases than the third- generation cephalosporins. Many can cross the blood-brain barrier and are effective in meningitis. They are also used against Pseudomonas aeruginosa. Cefepime Cefpirome Cefiderocol
  21. 21. Cefepime Cefpirome Cefiderocol
  22. 22. 5. Fifth generation: These new drugs are the only β-lactam antibiotics that are effective against methicillin-resistant-Staphylococcus-aureus (MRSA). Ceftobiprole Ceftaroline Ceftozolone Ceftobiprole Ceftaroline
  23. 23. Ceftozolone
  24. 24. Mechanism of action Cephalosporins are bactericidal and are less susceptible to hydrolysis by β-lactamases compared to penicillin antibiotics. Cephalosporins disrupt the synthesis of the peptidoglycan layer forming the bacterial cell wall.The peptidoglycan layer is important for cell wall structural integrity. The final transpeptidation step in the synthesis of the peptidoglycan is facilitated by penicillin-binding proteins (PBPs). PBPs bind to the D-Ala- D-Ala at the end of muropeptides (peptidoglycan precursors) to crosslink the peptidoglycan. Beta-lactam antibiotics mimic the D-Ala-D-Ala site, thereby irreversibly inhibiting the PBP mediated crosslinking of the peptidoglycan.
  25. 25. In absence of cephalosporins
  26. 26. In presence of cephalosporins
  27. 27. Video:
  28. 28. Therapeutic Uses ENT, upper respiratory and cutaneous infections Septicaemia (e.g., cefuroxime, cefotaxime) Pneumonia caused by susceptible organisms Meningitis (e.g.,cefriaxone, cefotaxime) Biliary tract infection Urinary tract infection (especially in pregnancy, or in patients unresponsive to other drugs) Sinusitis (e.g., cefadroxil)
  29. 29. Surgical prophylaxis Typhoid fever Penicillinase producing Staphylococcus infections Urinary tract infection Soft tissue infections caused by gram -ve bacteria
  30. 30. Structure Activity Relationships
  31. 31. 7-Acylamino substitution a. The addition of amino group and a hydrogen to α and α1 position produces basic compound, which is protonated under acidic conditions of stomach. The ammonium ion improves the stability of β-lactum of cephalosporins and make active orally. Activity against positive bacteria is increased and gram negative is decreased by acylation of amino group. b. When the new acyl groups are derived from carboxylic acids, it shows good spectrum of antibacterial action for gram-positive bacteria. c. Substitutions on the aromatic ring phenyl that increase lipophilicity provide higher gram-positive activity and generally lower gram-negative activity.
  32. 32. d. The phenyl ring in the side chain can be replaced with other heterocycles with improved spectrum of activity and pharmacokinetic properties; these include thiophene, tetrazole, furan, pyridine, and aminothiazoles. e. The L-isomer of an α-amino α1 -hydrogen derivative of cephalosphorins was 30–40 fold stable than D- isomer. Addition of methoxy oxime to α and α1increases the stability to nearly 100-fold. The presence of catechol grouping can also enhance activity, particularly, against Pseudomonas aeruginosa, and also retain some gram-positive activity, which is unused for a catechol cephalosporin.
  33. 33. Modification in the C-3 substitution: The pharmacokinetic and pharmacodynamics depends on C-3 substituents. Modification at C-3 position has been made to reduce the degradation (lactone of desacetyl cephalosporin) of cephalosporins. a.The benzoyl ester displayers improved gram-positive activity, but lowered gram-negative activity. b. Pyridine, imidaozle replaced acetoxy group by azide ion yields derivative with relatively low gramnegative activity. c. Displacement with aromatic thiols of 3-acetoxy group results in an enhancement of activity against gram- negative bacteria with improved pharmacokinetic properties. d. Orally active compounds are produced by replacement of acetoxy group at C-3 position with CH3 and Cl.
  34. 34. Other modifications a. Methoxy group at C-7, shows higher resistance to hydrolysis by β-lactamase. b. Oxidation of ring spectrum to sulphoxide or sulphone greatly diminishes or destroys antibacterial activity. c. Replacement of sulphur with oxygen leads to oxacepam (latamoxet) with increased antibacterial activity, because of its enhanced acylating power. Similarly, replacement of sulphur with methylene group (loracavet) has greater chemical stability and a longer half-life. d. The carboxyl group position-4 has been converted into ester prodrugs to increase bioavailability of cephalosporins, and these can be given orally as well. e. The antibacterial activity depends on the olefinic linkage at C-3 and C-4 position and their activity is lost due to the ionization of double bond to 2nd and 3rd positions.
  35. 35. Chemical degradation
  36. 36. R
  37. 37. Adverse Effects