Hhh

• Cephalosporins

  Naturally occurring cephalosporin is cephalosporin C

  
• Cephalosporin C


  • Not particularly potent compared with penicillins (1/1000 the activity of penicillin G)
  • Antibacterial activity is more evenly directed against Gram-negative and Gram-positive bacteria
  • Greater resistance to acid hydrolysis and β-lactamase enzymes
  • Less likely to cause allergic reactions

  
• Cephalosporin C was seen as a useful lead compound for the development of further broad-spectrum antibiotics, hopefully with increased potency

  
• Semisynthetic modifications of the basic 7-ACA nucleus

  1. Acylations of the 7-amino group with different acids

  2. Nucleophilic substitution

  3. Reduction of the acetoxyl group

  
• Chemical Degradation


  Cephalosporins experience various hydrolytic degradation reactions

  
• 1. acylaminocephalosporanic acid derivatives


  • The 3-acetoxylmethyl group is the most reactive site
  • The acetoxyl function readily undergoes solvolysis in strongly acidic solutions to form the desacetylcephalosporin derivatives
  • The desacetylcephalosporin lactones are virtually inactive

  
• 1. acylamino group of some cephalosporins


  • Can be hydrolyzed under enzymatic (acylases) and possibly nonenzymatic conditions to give 7-ACA (or 7-ADCA) derivatives

  
• Cephalosporins

  • The reactive functionality common to all is the β-lactam
  • Hydrolysis of the β-lactam gives initially cephalosporoic acids or possibly anhydrodesacetylcephalosporoic acids (7-ADCA, for the 7-acylaminocephalosporanic acids)

  
• Cephalosporins

  • Similar to penicillins
  • The β-lactam ring is crucial to the mechanism
  • The carboxylic acid at position 4 is important to binding
  • The bicyclic system is important in increasing ring strain
  • Stereochemistry is important
  • The acetoxy substituent is important to the mechanism

  
• Possible modifications to cephalosporins

  • Variations of the 7-acylamino side chain
  • Variations of the 3-acetoxymethyl side chain
  • Extra substitution at carbon 7

  
• 1. ACA

  Generation of 7-ACA requires hydrolysis of a relatively unreactive secondary amide in the presence of a labile β-lactam ring

  
• Generation of 7-ACA

  1. Protecting group

  2. Imino chloride formation

  3. Imino ether formation

  4. Hydrolysis to give 7-ACA

  
• Mechanism of action

  The acetoxy group acts as a good leaving group and aids the mechanism
• Oral cephalosporins

  • The oral activity is attributed to increased acid stability of the lactam ring, resulting from the presence of a protonated amino group on the 7-acylamino portion of the molecule
  • Absence of the leaving group at the 3-position is also important for high acid stability and good oral activity

  
• Cephaloglycin

  • Despite the presence of the phenylglycyl side chain, it is poorly absorbed orally, presumably because of solvolysis of the 3-acetoxyl group in the low pH of the stomach

  
• 1. hydroxyl derivatives and lactones of cephalosporins

  • Considerably less active in vitro than the parent cephalosporins
• Cephaloridine

  The pyridinium group is a metabolically stable leaving group, but cephaloridine is poorly absorbed through the gut wall and has to be injected

  
• Cefalexin

  The methyl substituent at position 3 appears to help oral absorption

  
• Cephalosporins

  • Broad-spectrum antibiotics with patterns of antibacterial effectiveness comparable to ampicillin
  • Much more resistant to inactivation by β-lactamases, particularly those produced by Gram-positive bacteria, than ampicillin
  • Ampicillin is generally more active against non-β-lactamase-producing strains of Gram-positive and Gram-negative bacteria sensitive to both it and the cephalosporins

  
• Cephalosporins


  • Susceptibility to various lactamases varies considerably
  • Significantly less sensitive than all but the β-lactamase-resistant penicillins to hydrolysis by the enzymes from S. aureus and Bacillus subtilis
  • The "penicillinase" resistance is a property of the bicyclic cephem ring system rather than of the acyl group

  
• Cephalosporins

  • Considerable variation in rates of hydrolysis by staphylococcal β-lactamase, with cephalothin and cefoxitin being the most resistant, and cefazolin the least resistant

  
• Cephalosporins

  • Introduction of polar substituents in the aminoacyl moiety confers stability to some β-lactamases
  • Alkoximino function in the aminoacyl group and a methoxyl substituent at the 7-position with α stereochemistry confer broadly based resistance to β-lactamases

  
• Generations of cephalosporins


  • First-generation
  • Second-generation
  • Third-generation
  • Fourth-generation
  • Fifth-generation
• First-generation cephalosporins

  • More active than penicillin G vs. some Gram-negative bacteria
  • Less likely to cause allergic reactions
  • Useful vs. penicillinase producing strains of S. aureus
  • Not active vs. Pseudomonas aeruginosa
  • Poorly absorbed from GIT, administered by injection
  • Metabolised to give a free 3-hydroxymethyl group which is less active

  
• Cephaloridine

  • The pyridine ring is a good leaving group, but cephaloridine is poorly absorbed through the gut wall and has to be administered by injection

  
• Cefalexin

  • The methyl group at position 3 is not a good leaving group and is bad for activity
• 4th-generation

  Cefepime and cefpirome
• First Generation Cephalosporins

  • Cephalothin

  
• Cephalothin

  • More active than penicillin G vs. some Gram -ve bacteria
  • Less likely to cause allergic reactions
  • Useful vs. penicillinase producing strains of S. aureus
  • Not active vs. Pseudonomas aeruginosa
  • Poorly absorbed from GIT
  • Administered by injection
  • Metabolised to give a free 3-hydroxymethyl group (deacetylation)
  • Metabolite is less active
• Cephalothin - drug metabolism

  1. Metabolism

  2. Less active (OH is a poorer leaving group)

  
• Cephaloridine

  • The pyridine ring is a good leaving group (neutralisation of charge)
  • Exists as a zwitterion and is soluble in water
  • Poorly absorbed through the gut wall
  • Administered by injection

  
• Cefalexin

  • The methyl group at position 3 is not a good leaving group
  • The methyl group is bad for activity but aids oral absorption
  • Cefalexin can be administered orally
  • A hydrophilic amino group at the alpha-carbon of the side chain helps to compensate for the loss of activity due to the methyl group

  
• First Generation Cephalosporins

  • Cefazolin
  • Cefadroxil
  • Cefuroxime

  
• Second Generation Cephalosporins (Oximinocephalosporins)

  • Greater Gram-negative spectrum while retaining some activity against Gram-positive cocci
  • More resistant to beta-lactamase

  
• Second Generation Cephalosporins

  • Cefaclor
  • Cefonicid
  • Cefprozil
  • Cefuroxime

  
• Cefuroxime

  • Cefuroxime sodium salt (parenteral)
  • Cefuroxime axetil (oral)
• Second Generation Cephalosporins

  • Cefotetan
  • Cefoxitin
  • Cefuroxime (parenteral)
  • Cefaclor
  • Cefprozil
  • Cefuroxime axetil
  • Loracarbef (oral)

  
• Second Generation Cephalosporins


  • Aminothiazole ring enhances penetration of cephalosporins across the outer membrane of Gram -ve bacteria
  • May also increase affinity for the transpeptidase enzyme
  • Good activity against Gram -ve bacteria
  • Variable activity against Gram +ve cocci
  • Variable activity vs. P. aeruginosa

  
• Third Generation Cephalosporins (Oximinocephalosporins)

  • Cefotaxime
  • Ceftazidime
  • Ceftizoxime
  • Ceftriaxone (parenteral)
  • Cefdinir
  • Cefditoren
  • Cefpodoxime proxetil
  • Ceftibuten
  • Cefixime (oral)
• Third Generation Cephalosporins


  • Zwitterionic compounds
  • Enhanced ability to cross the outer membrane of Gram negative bacteria
  • Good affinity for the transpeptidase enzyme
  • Low affinity for some b-lactamases
  • Active vs. Gram +ve cocci and a broad array of Gram -ve bacteria
  • Active vs. P. aeruginosa
  • Parenterally effective