Beta Lactams

• Bactericidal


  An antimicrobial drug that can eradicate an infection in the absence of host defense mechanisms; kills bacteria
• Bacteriostatic


  An antimicrobial drug that inhibits antimicrobial growth but requires host defense mechanisms to eradicate the infection; does not kill bacteria
• Beta-lactam antibiotics


  Drugs with structures containing a beta-lactam ring: includes the penicillins, cephalosporins and carbapenems. This ring must be intact for antimicrobial action
• Beta-lactamases


  Bacterial enzymes (penicillinases, cephalosporinases) that hydrolyze the beta-lactam ring of certain penicillins and cephalosporins
• Beta-lactam inhibitors


  Potent inhibitors of some bacterial beta-lactamases used in combinations to protect hydrolyzable penicillins from inactivation
• Minimal inhibitory concentration (MIC)


  Lowest concentration of antimicrobial drug capable of inhibiting growth of an organism in a defined growth medium
• Penicillin-binding proteins (PBPs)


  Bacterial cytoplasmic membrane proteins that act as the initial receptors for penicillins and other beta-lactam antibiotics
• Peptidoglycan


  Chains of polysaccharides and polypeptides that are cross-linked to form the bacterial cell wall
• Selective toxicity


  More toxic to the invader than to the host; a property of useful antimicrobial drugs
• Transpeptidases


  Bacterial enzymes involved in the cross-linking of linear peptidoglycan chains, the final step in cell wall synthesis
• Microbial resistance mechanisms

  • Production of antibiotic-inactivating enzymes
  • Changes in the structure of target receptors
• Microbial resistance mechanisms

  • Increased efflux via drug transporters
  • Decreases in the permeability of microbes' cellular membrane to antibiotics
• Chemotherapeutic agent strategies

  • Use of adjunctive agents that can protect against antibiotic inactivation
  • Use of antibiotic combinations
• Chemotherapeutic agent strategies

  • Introduction of new (and often expensive) chemical derivatives of established antibiotics
  • Efforts to avoid indiscriminate use or misuse of antibiotics
• Microorganisms and antimicrobials

  • Bacteria - Antibacterial
  • Viruses - Antiviral
  • Fungi - Antifungal
  • Parasites - Antiparasitic
• Beta-lactam antibiotics


  Major antibiotics that inhibit cell wall synthesis
• Beta-lactam antibiotics

  • Penicillins
  • Cephalosporins
• Beta-lactams


  Antibiotics with an unusual 4-member ring that is common to all members
• Penicillin G (benzylpenicillin)


  Most effective, widely used, well-tolerated
• Other cell wall synthesis inhibitors

  • Vancomycin
  • Fosfomycin
  • Bacitracin
• Penicillins


  • Narrow Spectrum Penicillinase susceptible
  • Penicillinase resistant
  • Wider Spectrum
• Cephalosporins


  • Narrow Spectrum 1st Generation
  • 2nd, 3rd and 4th Generation
  • Wider Spectrum
• Miscellaneous cell wall synthesis inhibitors

  • Carbapenem
  • Aztreonam
• Penicillins


  Derivatives of 6-aminopenicillanic acid containing a beta-lactam ring structure essential for antibacterial activity
• Penicillins


  Subclasses have additional chemical substituents that confer differences in antimicrobial activity, susceptibility to acid and enzymatic hydrolysis, and biodisposition
• Penicillins


  Vary in resistance to gastric acid, oral bioavailability, and are polar compounds not extensively metabolized
• Penicillins


  Excreted unchanged in urine via glomerular filtration and tubular excretion, which is inhibited by probenecid
• Penicillins


  Ampicillin and Nafcillin are partly excreted in bile, with plasma half-lives varying from 30 min to 1 h
• Procaine and Benzathine Penicillin G

  Given intramuscularly, have long half-lives as the drug is released slowly, and can cross the blood-brain barrier when meninges are inflamed
• Penicillins' mechanism of action

  1. Binding of the drug to specific receptors (penicillin-binding proteins [PBPs]) located in the bacterial cytoplasmic membrane

  2. Inhibition of Transpeptidase enzymes that act to cross-link linear peptidoglycan chains

  3. Activation of autolytic enzymes that cause lesions in the bacterial cell wall
• Enzymatic hydrolysis of the beta-lactam ring

  Results in the lost of antibacterial activity
• Penicillin resistance mechanisms


  • Beta-lactamases (penicillinases)
  • Structural changes in target PBPs
  • Changes in the porin structure in the outer membrane
• Beta-lactamase inhibitors


  Used in combination with penicillin to prevent their inactivation (e.g. clavulanic acid, sulbactam, tazobactam)
• Clinical uses of penicillins

  • Narrow-spectrum penicillinase-susceptible agents (e.g. Penicillin G)
  • Very-narrow-spectrum penicillinase-resistant agents (e.g. Methicillin, Nafcillin, Oxacillin)
• Penicillin G


  Prototype, parenteral, limited spectrum, susceptible to beta-lactamases
• Infections treated with Penicillin G

  • Streptococci
  • Meningococci
  • Gram (+) bacilli
  • Spirochetes
• Penicillin-resistant S. pneumoniae (PRSP) strains and some S. aureus and N. gonorrhea strains are resistant via production of beta-lactamases
• Penicillin G is the drug of choice for syphilis, and its activity against enterococci is enhanced by aminoglycoside
• Penicillin V


  Oral, used for oropharyngeal infections
• Methicillin, Nafcillin, Oxacillin


  Very-narrow-spectrum penicillinase-resistant agents used for known or suspected staphylococcal infections