microbio

• Salvarsan


  The first antimicrobial agent in the world, a remedy for syphilis synthesized by Ehrlich in 1910

  
• Sulfonamides


  Synthetic compounds developed by Domagk and other researchers in 1935, with limitations in terms of safety and efficacy
• The introduction of antibiotics into clinical practice revolutionized the treatment and management of infectious diseases
• Before the introduction of antibiotics, infectious diseases were the leading cause of morbidity and mortality in human populations
• Main antimicrobial classes


  • Arsphenamine
  • β-lactams
  • Sulphonamides
  • Polypeptides
  • Aminoglycosides
  • Tetracyclines
  • Amphenicols
  • Lipopeptides
  • Macrolides
  • Oxazolidinones
  • Glycopeptides
  • Streptogramins
  • Ansamycins
  • Quinolones
  • Lincosamides

  
• The introduction of certain antimicrobial classes affected the morbidity and mortality rates due to bacterial infectious diseases in human populations

  
• Problems of resistance to antibiotics of different classes are also extensively discussed
• Penicillin


  A safe and effective treatment for a multitude of infections since its introduction during World War II
• Over time, many bacteria have designed ways to defeat penicillin
• Scientists have continued to develop new types of penicillins, as well as other antibiotics that are able to overcome most of the bacterial defenses
• Beta-lactam ring


  All penicillin-family antibiotics have this, which is why they are also called the beta lactam antibiotics

  
• Mechanism of action of penicillins

  1. Inhibit bacterial cell wall synthesis by binding and inactivating proteins (penicillin binding proteins) present in the bacterial cell wall

  2. Inhibit the transpeptidation reaction and block cross-linking of the cell wall

  3. Kill bacteria through binding of the beta lactam ring to DD-transpeptidase, inhibiting its cross-linking activity and preventing new cell wall formation
• Without a cell wall, a bacterial cell is vulnerable to outside water and molecular pressures, and quickly dies
• Porins


  Channels in gram-negative bacteria that the penicillin beta-lactam ring must pass through to bind to and competitively inhibit the transpeptidase enzyme
• Requirements for beta-lactam penicillins to be effective

  • Penetrate the cell layers
  • Keep its beta-lactam ring intact
  • Bind to the transpeptidase (penicillin-binding protein)
• Ways bacteria defend themselves from the penicillin family

  • Gram-negative bacteria: Preventing the penicillin from penetrating the cell layers by altering the porins
  • Both gram-positive and gram-negative bacteria: Having beta-lactamase enzymes that cleave the C-N bond in the beta-lactam ring
  • Altering the molecular structure of the transpeptidase so the beta lactam antibiotic cannot bind
• Anaphylactic reaction


  Acute allergic reaction that may occur from minutes to hours, is IgE-mediated, and can cause bronchospasm, urticaria, and anaphylactic shock
• Delayed rash


  More common allergic reaction that appears several days to weeks later
• All penicillin family antibiotics can cause diarrhea by destroying the natural GI flora and allowing resistant pathogenic bacteria (such as Clostridium difficile) to grow in their place

  
• Types of penicillin


  • Penicillin G
  • Aminopenicillins
  • Penicillinase-resistant penicillins
  • Antipseudomonal penicillins (including carboxypenicillins, ureidopenicillins, and monobactams)
  • Cephalosporins

  
• Penicillin G


  The original penicillin discovered by Fleming, usually given intramuscularly or intravenously in a crystalline form to increase its half-life
• Aminopenicillins


  Offer better coverage of gram-negative bacteria
• Penicillinase-resistant penicillins


  Useful against beta-lactamase producing Staphylococcus aureus

  
• Antipseudomonal penicillins


  Offer even wider coverage against gram negative bacteria, including Pseudomonas aeruginosa

  
• Cephalosporins


  A widely used group of antibiotics with a beta-lactam ring, resistant to beta-lactamase, and covering a broad spectrum of gram positive and gram-negative bacteria

  
• Many bacteria have now developed resistance to penicillin G because it is sensitive to beta-lactamase enzymes
• When penicillin G is still used

  • Pneumonia caused by Streptococcus pneumoniae
  • Streptococcus pharyngitis caused by group A beta hemolytic streptococcus

  
• Penicillin V


  An oral form of penicillin that is acid stable in the stomach
• Aminopenicillins (Ampicillin and Amoxicillin)


  Have a broader spectrum than Penicillin G, hitting more gram negative organisms due to better penetration through the outer membranes of gram-negative bacteria and better binding to the transpeptidase
• Resistance has developed, with 30% of Haemophilus influenzae and many enteric gram-negative bacteria acquiring penicillinase and becoming resistant

  
• Aminopenicillins


  One of the few drugs effective against the gram-positive enterococcus

  
• Amoxicillin


  More effectively absorbed orally than ampicillin, so frequently used for outpatient treatment of bronchitis, urinary tract infections, and sinusitis caused by gram-negative bacteria
• Ampicillin


  Commonly used intravenously with aminoglycosides (gentamicin) for broad gram-negative coverage, especially for serious urinary tract infections

  
• Penicillinase-resistant penicillins


  Highly efficacious against staphylococcal infections, used for gram-positive bacteria that produce penicillinase (Staphylococcus aureus)

  
• Penicillinase-resistant penicillins


  • Methicillin
  • Nafcillin
  • Oxacillin
• Anti-Pseudomonal penicillins (Carboxypenicillins and Ureidopenicillins)

  Have expanded gram negative rod coverage, especially against Pseudomonas aeruginosa, and are also active against anaerobes and many gram positives

  
• Anti-Pseudomonal penicillins


  • Ticarcillin and Carbenicillin (Carboxypenicillins)
  • Piperacillin and mezlocillin (Ureidopenicillins)

  
• Anti-Pseudomonal penicillins are combined with aminoglycosides to double up the Pseudomonas killing (synergism)
• Anti-Pseudomonal penicillins are sensitive to penicillinases, so most Staphylococcus aureus are resistant

  
• Beta-Lactamase Inhibitors (Clavulanic Acid, Sulbactam, and Tazobactam)


  Inhibitors of beta-lactamase that can be given in combination with penicillins to create a beta-lactamase resistant combination