penems

• comparison of penem and carbapenem

  • carbon has about half the diameter as that of sulfur
  • carbopenem ring thus is more strained than the penem ring
  • the fused beta lactam ring is thus more reactive and potent against PBPs
  • carbopenem is also less stable and easier to be hydrolyzed, thus prohibiting oral bioavailability

  
• thienamycin

  • not a real drug but the lead compound of carbapenem antibiotics
  • attractive properties:
  • extremely potent in vitro
  • broad-spectrum antimicrobial activity in vitro
  • very stable and even inhibitor to beta-lactamase d/t the alpha-oriented hydroxyethyl group
  • penetrates through porin (small zwitter ion)
  • shortcomings:
  • very unstable at acidic or alkaline pHs
  • concentration-dependent self-inactivation of beta-lactam ring in solution by the primary amine
  • hydrolysis by renal dehydropeptidase-I
  • half-life too short to be useful in vivo
• imipenem + silastatin (primaxin): a "precious", "reserved" antibiotics

  • improvements from thienamycin:
  • the primary amine group is replaced w/ a non-nucleophilic imine group
  • long enough plasma half-life (~ 1h) d/t the inhibition of renal dehydropeptidase-I by cilastatin
  • activities and clinical applications:
  • broader spectrum than any available antibiotics in US
  • orally inactive
  • induces the expression of beta-lactamase
  • seldom the first line drug but a reserved parenteral drug for special cases of serious infection
• second-generation carbapenems

  • meropenem (merrem)
  • used for about 10 yrs to treat CNS infections
  • also approved for complicated skin infections
  • stable to and even inhibitor to most beta-lactamases
  • small zwitter ions and penetrates through porins well
  • intrinsically stable to renal dehydropeptidase-I and is used alone
  • potent and broad-spectrum
  • "precious" antibiotic drugs usually reserved for serious hospital acquired infections that are resistant to other beta-lactams

  
• ertapenem (invanz)

  • one additional negative charge compared w/ other carbapenems
  • a longer serum half-life that allows once-daily dosing
  • inferior activity against gram negative P. aeruginosa and Acinetobacter spp.
  • its spectrum of activity against gram positive organisms, Enterobacteriaceae, and anaerobes makes it attractive for use in intra-abdominal and pelvic infections