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Cephalosporins 2


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  • 1. Cephalosporin s
  • 2. introduCtion
  • 3.  The cephalosporins are β-Lactam antibiotics that are closely related both structurally and functionally to the penicillins.  Mechanism of action, mechanism of resistance and some other properties of cephalosporins are identical to penicillins)  Cephalosporins are one of the most widely used antibiotics and are equal in importance to penicillin.
  • 4. • The cephalosporins are isolated from: - Cephalosprium species - Prepared semisynthetically. • In 1945 Giuseppe Brotzu`s discovered that cultures of Cephalosporium acremonium inhibited the growth of a wide variety of Gram-positive and Gram-negative bacteria.
  • 5. • In 1948 Abraham and his colleagues have been supplied cultures of the fungus and was isolated three principal antibiotic components: - Cephalosporin P, (a steroid antibiotic that resembles fusidic acid) with minimal antibacterial activity. - Cephalosporin N, later discovered to be identical with synnematin N (a penicillin derivative now called penicillin N) - Cephalosporin C.
  • 6. • Penicillin N (Cephalosporin N) *Most of the antibiotics introduced since 1965 have been semisynthetic cephalosporins.
  • 7. • Cephalosporin C can be hydrolyzed by acid to 7-aminocephalosporanic acid. *Compounds containing 7-aminocephalosporanic acid are: - Relatively stable in dilute acid. - Highly resistant to penicillinase, regardless of the nature of their side chains and their affinity for the enzyme. N S NH H H O HO O O CH3OO OH NH2 O Cephalosporin C N S O HO O O CH3ONH2 7- aminocephalosporinic acid 1 2 3 4 5 6 7 5 4 3 2 1 67
  • 8. This compound has been modified by the addition of different side chains to create a whole family of cephalosporin antibiotics.
  • 9. • Most cephalosporins are produced semisynthetically by the chemical attachment of side chains to 7-aminocephalosporanic acid. • Cephalosporins (7α-H) and cephamycins (7α-OCH3): Cephalosporins 1 2 3 4 5 6 N S O HO O X NH H R O 7 Cephamycin 1 2 3 4 5 6 N S O HO O X NH OCH3 R O 7 Most natural cephalosporin and cephamycin are not used clinically for side effects, but semi-synthetic products are used.
  • 10. Mechanism of action
  • 11. The mechanism of resisTance of m.o - Alteration of binding site. - Decrease permeability. - Production of β–lactamase enzymes (enzymatic inactivation).
  • 12. classificaTion of cephalosporins Cephalosporins have been classified as first, second, third and fourth generation largely on the basis of bacterial susceptibility patterns and resistance to β- lactamases: First generation Second generation Third generation Fourth generation Cephalothin Cephapirin Cefazolin Cephalexin* Cephradine* Cefadroxil Cefamandole Cefuroxime Cefonicid Ceforanide Cefaclor* Cefoxitin Cefotetan Cefprozil* Cepuroxime axetil* Cefmetazole Cefotaxime Ceftizoxime Ceftriaxone Ceftazidime Cefoperazone Cefixime* Cefpodoxime proxetil* Ceftibuten* Cefdinir* Cefepime Cefpirome Cefclidin * Oral agents
  • 13.  SAR of oral cephalosporin 1st and 2nd generation rucTure acTiviTy relaTionship  SAR of 3rd generation oral and parentral: 1- β-lactam ring responsible for action. 2- β-lactamase stability. 3- Potency and spectrum.
  • 14. Classification of cephalosporins
  • 15. First generation : *Cephalothin N S O NH C CH2OCCH3 C O O OH Cephalothin CH2 S O * Cefazolin N S O NH C CCH2 O O OH Cefazolin N N N NN S CH3CH2S
  • 16. * Cefazolin N S O NH C CCH2 O O OH Cefazolin N N N NN S CH3CH2S *Cephalexin N S O NH CH3 C CCH O O OH NH2 Cephalexin
  • 17. * Cephradine N S O NH CH3 C CCH O O OH NH2 Cephradine * Cefadroxil N S O NH CH3 C CCH O O OH HO NH2 Cefadroxil
  • 18. Second generation: * Cefamandole N S O NH C C O O OH Cefamandole N NN N CH2S CH3 CH OH * Cefoxitin N S OCH3 O NH C CH2OCNH2 CCH2 S O O O OH Cefoxitin
  • 19. * Cefaclor N S O NH Cl C CCH O O OH NH2 Cefachlor * Cefuroxime N S O NH C CH2OCNH2 C O O OH Cefuroxime C NOCH3 O O
  • 20. * Cefuroxime axetil N S O NH C CH2OCNH2 C O O Cefuroxime axetil C NOCH3 O O O CHOCCH3 O CH3 * Cefonicid N S O NH C C O O OH Cefonicid N NN N CH2S CH2SO3H CH OH
  • 21. * Cefotetan N S O NH C CH3O C O O OH Cefotetan N N NN CH2S CH3 S S C C C O O H2N HO * Ceforanide N S O NH C C O O OH Ceforanide N NN N CH2S CH2CO2H CH2 CH2NH2
  • 22. * Cefmetazole N S O NH C CH3O C O O OH Cefmetazole NCCH2SCH2 N N NN CH2S CH3
  • 23. Third generation: *Cefotaxime N S CH2OCCH3 C O NH OHO OCC O NOCH3 S NH2N Cefotaxime *Ceftizoxime N S O NH C H C O O OH Ceftizoxime C NOCH3 S N H2N
  • 24. N S O NH C C O O OH Ceftriaxone C NOCH3 S N H2N N N N OH CH2S O CH3 *Ceftriaxone *Cefixime N S NH C CH=CH2 O CC S N H2N O O OH Cefixime NOCH2CO2H
  • 25. *Cefpodoxime proxetil N S NH CH2OCH3 C O C O O NOCH3 Cefpodoxime proxetil S N H2N C O CHOCOCH(CH3)2 O CH3
  • 26. Third generation cephalosporins with good activity against Pseudomonas: *1-Cefoperazone N S O NH C CH2S C O O OH Cefoperazone C S N H2N NH C N N O O O C2H5 N N N N CH3 *2-Ceftazidime N S O NH C C O O OH Ceftazidime C S N H2N N O C CO2HCH3 CH3 N CH2 +
  • 27. Fourth Generation Cephalosporins: * Cefpirome NN S HN O H H CO2 CC N S H2N N O - OCH3 Cefpirome +3 N S HN O H H CO2 N CC N S H2N N O - OCH3 Cefepime H3C + * Cefepime
  • 28. Pharmacokinetics 1- Administration: All cephalosporins except cefadroxil, cephalexin, cephradine, cefaclor, cefuroxime axetil, cefdinir, cefixime and ceftibuten must be administered intravenously because of their poor oral absorption. 2- Distribution: - All of cephalosporins distribute very well into body fluids. However, several cephalosporins penetrate into CSF in sufficient concentration to be useful for the treatment of meningitis. These include: Cefuroxime (2nd gen.), ceftriaxone, cefotaxime and ceftizoxime (3rd gen.).
  • 29. 3- Fate: - Elimination occurs through tubular secretion and/or glomerular filtration. Cefoperazone are excreted through the bile and are frequently used in patients with renal insufficiency.
  • 30. Adverse reactions The most common adverse reactions are: 1- Allergic and hypersensitivity reactions 2- A disulfiram-like effect 3-Bleeding: - Bleeding can occur with cefamandole, cefotetan, cefmetazole moxalactam and cefoperazone (containing an N-methyl-5- thiotetrazole moiety at the 3 position) b/c of antivitamin K effects, administration of the vitamin corrects the problem. 4- Nephrotoxicity.
  • 31. Therapeutic uses - When Gm +ve bacteria is involved a 1st generation agents is preferable. - When the pathogen is gm –ve and the infection is serious parentral use of a 3rd generation agent is recommended. First generation cephalosporins are: • Excellent agents for skin and soft tissue infections due to S. aureus and S. Pyogenes. • A single dose of cefazolin just before surgery is the preferred as prophylaxis
  • 32. Second-generation cephalosporins • The second generation agents have inferior activity against penicillin-resistant S. pneumoniae compared to either the 3rd generation agents or ampicillin and therefore should not be used for treatment of meningitis or pneumonia. • In case where Gm -ve bacteria and anaerobes are involved such as intraabdominal infections, pelvic inflammatory disease and diabetic foot infection, cefoxitin and cefotetan have been shown to be effective. • For colorectal surgery where prophylaxis for intestinal anaerobes is desired, cefoxitin or cefotetan (2nd generation) are preferred.
  • 33. Third generation cephalosporins • Third generation cephalosporins have been considered to be the drugs of choice for serious infections caused by: Klebsiella, Enterobacter, Proteus, Haemophilus species. • Ceftriaxone is now the drug of choice for all form of gonorrhea. • Cefotaxime or ceftriaxone (as part of a 3-drug combination with vancomycin and ampicillin) are used for the initial treatment of meningitis in nonimmunocompromised adults and children older than 3 months.
  • 34. • Ceftazidime + aminoglycoside is the drug of choice for Pseudomonas meningitis. • The antimicrobial spectrum of cefotaxime and ceftriaxone is excellent for the treatment of community acquired pneumonia, i.e. that caused by pneumococci, H. influenzae, S. aureus. Third generation cephalosporins (Cont.)
  • 35. The fourth generation • The fourth generation are indicated for the empirical treatment of nosocomial infections where antibiotic resistance due to extended spectrum β-lactamases are anticipated. e.g. cefepime has superior activity against nosocomial isolates of Enterobacter, Citrobacter compared to ceftazidime and piperacillin