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Beta-lactams

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Carbapenems
Cephalosporins
ESBL
Penicillins

Beta-lactams

Classes

  • Penams eg penicillins
  • Clavams: beta-lactamase inhibitors that contain a five-membered ring with an oxygen heteroatom (eg clavulanic acid)
  • Carbapenems eg meropenem, imipenem
  • Cephems (cephalosporins)
  • Monobactams eg aztreonam
  • Oxacephems: oxygen analogues of cephems

Mode of action

Bacteriostatic effect due inhibition of cell wall synthesis by inactivation of transpeptidases. This is a crucial enzyme in the cross-linking of peptidoglycan - the basic building block of the cell wall

  • act as a false substrate for D-alanyl-D-alanyl transpeptidases
  • requires carboxylate or sulfonate group of beta-lactam to react the a serine residue of transpeptidases (also known as penicillin-binding proteins) to give an inactive acylated enzyme
  • transpeptidases are located in periplasmic space. This is directly accessible in Gram +ve bacteria but in Gram -ves the drugs need to cross the outer bacterial cell membrane (passive diffusion) or pass through porin channels

Bactericidal effect results from indirect mechanisms (mostly activation of autolytic enzymes)

Only active against rapidly dividing bacteria.

Resistance

  • alteration in porin channels limits access to transpeptidases in gram negative bacteria
  • modification of transpeptidases resulting in decreased affinity for beta-lactams (eg MRSA)
  • production of beta-lactamases (most common mechanism). These hydrolyse beta-lactams at a far higher rate than transpeptidases (1000 beta-lactams per second cf. 1 per hour). Many beta-lactams have been made resistant to beta-lactams but beta-lactamases with activity against these new drugs inevitably develop
    • extended spectrum beta-lactamases are a particular problem. They are capable of hydrolysing penicillins, broad-spectrum cephalosporins and monobactams. Often associated with resistance to aminoglycosides and fluoroquinolones

Pharmacodynamics

Further reading

Van Bambeke F. Mechanisms of action. In Armstrong D, Cohen J. Infectious diseases. Mosby, London, 1999, pp7/1.1-7/1.14


©Charles Gomersall, April, 2014 unless otherwise stated. The author, editor and The Chinese University of Hong Kong take no responsibility for any adverse event resulting from the use of this webpage.
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