Ketz.antivirals

• 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
• 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-lactamases


  Bacterial enzymes (penicillinases, cephalosporinases) that hydrolyze the beta-lactam ring of certain penicillins and cephalosporins; confer resistance
• 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
• Penicillins


  • All penicillins are derivatives of 6-aminopenicillanic acid and contain a beta-lactam ring structure that is essential for antibacterial activity
  • Penicillin subclasses have additional chemical substituents that confer differences in antimicrobial activity, susceptibility to acid and enzymatic hydrolysis, and biodisposition
• Penicillin Pharmacokinetics


  • Penicillins vary in their resistance to gastric acid and therefore vary in their oral bioavailability
  • Penicillins are polar compounds and are not metabolized extensively
  • They are usually excreted unchanged in the urine via glomerular filtration and tubular secretion
• Mechanism of Action of Beta-Lactam Antibiotics


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

  2. Inhibition of the transpeptidation reaction that cross-links the linear peptidoglycan chain constituents of the cell wall

  3. Activation of autolytic enzymes that cause lesions in the bacterial cell wall
• Resistance to Beta-Lactam Antibiotics


  • Enzymatic hydrolysis of the beta-lactam ring results in loss of antibacterial activity
  • Formation of beta-lactamases (penicillinases) by most staphylococci and many Gram-negative organisms is a major mechanism of bacterial resistance
  • Structural change in target PBPs is another mechanism of resistance and is responsible for methicillin resistance in staphylococci and for resistance to penicillin G in pneumococci and enterococci
  • Changes in the porin structures in the outer cell wall membrane may contribute to resistance in some Gram-negative rods by impeding access of penicillins to PBPs
• Narrow-spectrum penicillinase-susceptible penicillins


  • Penicillin G
  • Penicillin V
• Narrow-spectrum penicillinase-susceptible penicillins


  Have a limited spectrum of antibacterial activity and are susceptible to beta-lactamases
• Very-narrow-spectrum penicillinase-resistant penicillins


  • Methicillin
  • Nafcillin
  • Oxacillin
• Very-narrow-spectrum penicillinase-resistant penicillins


  Their primary use is in the treatment of known or suspected staphylococcal infections
• Wider-spectrum penicillinase-susceptible penicillins


  • Ampicillin
  • Amoxicillin
  • Piperacillin
  • Ticarcillin
• Wider-spectrum penicillinase-susceptible penicillins


  Have a wider spectrum of antibacterial activity than penicillin G but remain susceptible to penicillinases
• Cephalosporin generations


  • First generation
  • Second generation
  • Third generation
  • Fourth generation
• Cephalosporin generations


  Correspond to the order of their introduction into clinical use and loosely with extended Gram-negative coverage
• Cephalosporin Pharmacokinetics


  • Several cephalosporins are available for oral use, but most are administered parenterally
  • Cephalosporins with side chains may undergo hepatic metabolism, but the major elimination mechanism is renal excretion via active tubular secretion
  • Most first- and second-generation cephalosporins do not enter the cerebrospinal fluid even when the meninges are inflamed
• Mechanism of Action of Cephalosporins

  Cephalosporins bind to PBPs on bacterial cell membranes to inhibit bacterial cell wall synthesis by mechanisms similar to those of the penicillins
• Cephalosporin Resistance


  • Structural differences from penicillins render cephalosporins less susceptible to penicillinases produced by staphylococci, but many bacteria are resistant through the production of other beta-lactamases that can inactivate cephalosporins
  • Resistance can also result from decreases in membrane permeability to cephalosporins and from changes in PBPs
  • Methicillin-resistant staphylococci are also resistant to cephalosporins
• First-generation cephalosporins


  • Cefazolin
  • Cephalexin
• First-generation cephalosporins


  Active against Gram-positive cocci, including staphylococci and common streptococci, and many strains of E coli and K pneumoniae
• Second-generation cephalosporins


  • Cefaclor
  • Cefuroxime
  • Cefprozil
• Second-generation cephalosporins


  Usually have slightly less activity against Gram-positive organisms than the first-generation drugs but have an extended Gram-negative coverage
• Third-generation cephalosporins


  • Ceftazidime
  • Cefoperazone
  • Cefotaxime
• Third-generation cephalosporins


  Have increased activity against Gram-negative organisms resistant to other beta-lactam drugs and ability to penetrate the blood-brain barrier (except cefoperazone and cefi)
• Penicillins and cephalosporins are the major antibiotics that inhibit bacterial cell wall synthesis
• More than 50 antibiotics that act as cell wall synthesis inhibitors are currently available
• The selective toxicity of the drugs discussed in this chapter is mainly due to specific actions on the synthesis of a cellular structure that is unique to the microorganism
• First-generation cephalosporins


  • Minimal activity against Gram-negative cocci, enterococci, methicillin-resistant staphylococci, and most Gram-negative rods
• Second-generation cephalosporins


  • Usually have slightly less activity against Gram-positive organisms than first-generation drugs but have an extended Gram-negative coverage
  • Marked differences in activity occur among the drugs in this subgroup
• Clinical uses of second-generation cephalosporins

  • Infections caused by the anaerobe Bacteroides fragilis (cefotetan, cefoxitin)
  • Sinus, ear, and respiratory infections caused by H influenzae or M catarrhalis (cefamandole, cefuroxime, cefaclor)
• Third-generation cephalosporins


  • Increased activity against Gram-negative organisms resistant to other beta-lactam drugs
  • Ability to penetrate the blood-brain barrier (except cefoperazone and cefixime)
  • Active against Providencia, Serratia marcescens, and beta-lactamase-producing strains of H influenzae and Neisseria
  • Less active against Enterobacter strains that produce extended-spectrum beta-lactamases
  • Ceftriaxone and cefotaxime are currently the most active cephalosporins against penicillin-resistant pneumococci (PRSP strains)
  • Cefoperazone and ceftizoxime have activity against Pseudomonas and B fragilis
• Fourth-generation cephalosporins


  • More resistant to beta-lactamases produced by Gram-negative organisms, including Enterobacter, Haemophilus, Neisseria, and some penicillin-resistant pneumococci
  • Cefepime combines the Gram-positive activity of first-generation agents with the wider Gram-negative spectrum of third-generation cephalosporins
  • Ceftaroline has activity in infections caused by methicillin-resistant staphylococci
• Allergy to cephalosporins


  • Cephalosporins cause a range of allergic reactions from skin rashes to anaphylactic shock
  • These reactions occur less frequently with cephalosporins than with penicillins
  • Complete cross-hypersensitivity between different cephalosporins should be assumed
  • Cross-reactivity between penicillins and cephalosporins is incomplete (5–10%), so penicillin-allergic patients are sometimes treated successfully with a cephalosporin
  • Patients with a history of anaphylaxis to penicillins should not be treated with a cephalosporin