cephalosporins

• cephalosporins

  • historically, they went a long way from development to clinical success
  • today, thousands have been studied and more than twenty of them (five generations) are in significant use
  • their usage depends a lot on detailed empirical data of spectra of antibiotic activity
• why so many cephalosporins?

  • to fight against tough bugs
  • to broaden antimicrobial spectrum to gram negative bacteria
  • to increase activity against resistant microorganisms
  • increase stability in the presence of beta lactamases,
  • increase permeability across bacteria cells,
  • increase affinity to PBPs, etc.
  • to improve pharmacokinetic properties
  • oral bioavailability (acid stability, oral absorption)
  • tissue distribution
  • to minimize adverse effects
  • allergic and hypersensitivity reactions
  • severe bleeding in high risk pts
  • intolerance after parenteral administration
• classification of cephalosporins

  • 1st generation: active in vitro against gram positive cocci, group A and group B hemolytic streptococci and S. pneumoniae
  • not effective against MRSA
  • mostly inactive against gram negative
  • 2nd generation: retain activity of the 1st generation plus H. influenzae
  • better anti gram negative activities
• classification of cephalosporins (cont.)

  • 3rd generation: less active against gram positive but much more active against gram negative, including multi-drug resistant, hospital acquired stains, not active against Pseudomonas aeruginosa except for ceftazidime
  • 4th generation: similar to the 3rd generation but more active against Pseudomonas aeruginosa and some enterobacteria that are resistant to 3rd generation cephalosporins
  • 5th generation: activities against MRSA and other multi-drug resistant
• the medicinal chemistry of cephalosporins

  • to point out certain structural features of the clinically important cephalosporins in order to help you rationally memorize the properties of the clinically important cephalosporins
• drawbacks of a leaving group at C3 [on cephalosporins]:

  1. facilitates non-enzymatic hydrolysis of the beta lactam ring, thus lowering oral bioavailability
  2. the N-methyl-5-thiotetrazole (MTT) leaving group (eg, cefotetan, cefamandole, celmetazole, moxalactam and cefoperazone) have been implicated in a higher incidence of clotting difficulties and acute alcohol intolerance

  • such drugs should not be given to pts taking oral anticoagulants or heparin therapy
• structure feature #3: the syn-alkoximine

  • cephem nucleus w/ beta-lactam
  • -OR group and the beta lactam on the same side of the C=N double bond (like the "goat")
  • hinder the hydrolysis by many beta lactamases
  • cephem nucleus w/ the beta-lactam
  • the anti-isomer has little stabilizing effect against many beta lactamases

  
• structure feature #3: the syn-alkoximine (cont.)

  • beta lactam antibiotics w/ such function:
  • one 2nd generation cephalosporin - cefuroxime
  • all except two 3rd generation cephalosporins - cefotaxime, ceftizoxime, cetriaxone, ceftazidime, cefixime, cefpodoxime proxetil and cefdinir but not in cefbuten (although a bioistere thereof) or cefoperazone
  • 4th and 5th generation cephalosporins
  • monobactam: aztreonam and tigemonam
• ceftibuten (3rd generation)

  • the Z-olefinic methylene group (C=CHCH2-) is an isosteric replacement of the syn-oximine (C=NO-) group
  • retains the resistance to many beta lactamases
  • improved chemically stability
  • orally active
• structure features that contribute to the resistance of cephalosporins against inactivation by beta lactamases

  1. the cephem nucleus w/ a leaving group on the CH2 at C3 of the cephem nucleus (+)
  2. an alpha methoxy substitute at 7 position of the cephem nucleus (++)

  • cephamycins in 2nd generation cephalosporins

  3. a syn-alkoximine group its isosteric replacement in the aminoacyl side chain (+++)

  • most gen 3, 4, 5 cephalosporins
• structure feature #4: amine-containing substituent at 2 position

  • present in most gen 4, 5 Cef's
  • makes the Cef a zwitterion
  • promotes permeation across porin
  • promotes activities against Pseudomonas
• structure features for orally active cephalosporins

  • a basic amine on the carbon next to the carbonyl of the side chain (increase acid stability and absorption via intestinal dipeptide transporter, analogous to penicillins) BUT NP C3-CH2-X, where X is a good leaving group (increase acid stability)
  • exceptions: these are also orally active:
  • 1) prodrugs: cefuroxime axetil, cefpodoxime proxetil
  • 2) three 3rd generation agents:
  • ceftibuten - stable bioisostere of syn-alkoximine
  • cefdinir - used orally but not only 20 - 30% absorption
  • cefixime - quick absorption, somewhat surprising