USMLE Step 1 Review Pages 288-291 First Aid, 5 th Edition by Q719y1

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									USMLE Step 1 Review
Pages 288-291
First Aid, 5th Edition


      Monday, March 20th, 2006
      By Dip Jadav
Review of Definitions

     Bactericidal – a substance that kills
      organisms directly; severe, life-
      threatening, or complicated infections
      require treatment with bactericidal drugs.
     Bacteriostatic – a substance that stops
      further growth of an organism; mild,
      uncomplicated infections may be treated
      with bacteriostatic drugs.
Aminoglycosides – Gentamycin, Neomycin,
      Amikacin, Tobramycin, Streptomycin

    Mechanism of Action
        Bactericidal.
        Two main capabilities.
            Inhibit the formation of the initiation complex, thus depleting the
             available ribosomal pool and leading to decreased protein
             synthesis.
            Cause misreading (and subsequent mistranslation) of mRNA,
             leading to faulty or truncated proteins.
        Aminoglycoside entry to the cytoplasm is through oxygen-
         dependent active transport. Anaerobic bacteria are resistant
         through inability to take up the drug. Facultative anaerobes
         can be relatively resistant if they are in an anaerobic
         environment.
Aminoglycosides – Gentamycin, Neomycin,
Amikacin, Tobramycin, Streptomycin

     Clinical Use
         Severe gram-negative rod infections.
         Synergistic with β-lactam antibiotics. They
          have different mechanisms of action, and it
          has been noted that their efficacy is greater
          when used together than would be expected
          if used.
         Neomycin has been used orally to sterilize
          the bowel prior to surgery. This, however,
          does carry the risk of the development of
          antibiotic-associated colitis.
Aminoglycosides – Gentamycin, Neomycin,
      Amikacin, Tobramycin, Streptomycin


       Toxicity
           Nephrotoxicity, especially when used
            with cephalosporins due to their inherent
            nephrotoxicity.
           Ototoxicity, especially when used with
            loop diuretics due to their inherent
            ototoxicity.
Tetracyclines – Tetracycline, Doxycycline,
       Demeclocycline, Minocycline

     Mechanism of Action
         Bacteriostatic.
         Bind reversibly to the 30S subunit of
          ribosomes and reduce the affinity of the
          aminoacyl-tRNA for the mRNA-ribosome
          complex, preventing elongation of the protein
          being synthesized.
Tetracyclines – Tetracycline, Doxycycline,
       Demeclocycline, Minocycline

     Clinical Use
         Active against a broad spectrum of bacteria
          that are aerobic, anaerobic, gram-positive,
          and gram-negative and protozoa.
         VACUUM your BedRoom Tonight.
Tetracyclines – Tetracycline, Doxycycline,
       Demeclocycline, Minocycline

     Toxicity
         GI distress.
             Tetracyclines are irritative. They cause epigastric
              burning, abdominal distress, nausea, and vomiting.
         Discoloration of teeth and inhibition of bone growth.
             Deposition of tetracyclines into teeth and bones may
              result from chelation of the calcium in these tissues.
             They may retard skeletal development in the fetus and
              permanently discolor tooth enamel.
             This can follow administration to children less than 8
              years old or to pregnancy or nursing women, since
              tetracyclines can cross the placenta and into breastmilk.
Macrolides – Erythromycin, Azithromycin,
       Clarithromycin

     Mechanism of Action
         Bacteriostatic.
         Inhibit protein synthesis by blocking
          translocation (the movement of the
          elongated peptide from the A site to the P
          site).
Macrolides – Erythromycin, Azithromycin,
       Clarithromycin

     Clinical Use
         An alternative in the treatment of URIs in
          patients who are allergic to penicillin.
         STDs.
Macrolides – Erythromycin, Azithromycin,
       Clarithromycin

     Toxicity
         GI discomfort due to ability to act as an
          agonist at motilin receptors, increasing gut
          motility.
Chloramphenicol

    Mechanism of Action
        Bacteriostatic.
        Binds to the 50S subunit and inhibits the
         peptidyltransferase enzyme.
        This prevents the addition of new amino
         acids onto the growing peptide chain.
Chloramphenicol

    Clinical Use
        Meningitis. In general, due to its toxicities,
         use chlomaphenicol only in life-threatening
         infections when other drugs of choice cannot
         be used or when it is clearly superior.
Chloramphenicol

    Toxicity
        Gray baby syndrome – abdominal distention,
         vomiting, pallor, cyanosis, and circulatory
         collapse.
            It arises because the immature liver of the
             newborn or premature infant cannot conjugate
             chloramphenicol.
Clindamycin

    Mechanism of Action
        Bacteriostatic.
        Block peptide bond formation at the 50S
         ribosomal subunit.
            Specifically, they may inhibit binding of aminoacyl-
             tRNA or
            Inhibit the translocation reaction once the
             aminoacyl-tRNA is bound.
Clindamycin

    Clinical Use
        Highly effective against anaerobic bacteria,
         such as Clostridia and Bacteriodes.
Clindamycin

    Toxicity
        While highly efficacious against anaerobic
         infections, Clostridia are often more resistant
         than other anaerobes. The inability to
         eradicate C. dificile may contribute to the
         development of antibiotic-associated
         pseudomembranous colitis.
Sulfonamides – Sulfamethoxazole (SMX),
       Sulfisoxazole, Triple Sulfas

     Mechanism of Action
         Bacteriostatic.
         Sulfonamides are structurally related to PABA (para-
          aminobenzoic acid).
         They compete with PABA for the active site of the
          bacterial enzyme dihydropteroate synthetase.
         Dihydropteroate synthetase catalyzes the synthesis of
          dihydropteroic acid, an intermediate in the pathway to
          the synthesis of tetrahydrofolate (THF).
         THF acts as a coenzyme, which transports one-
          carbon units from one molecule to another.
             Needed in the synthesis of molecules such as Thymine,
              Purines, and f-Met-tRNA.
Sulfonamides – Sulfamethoxazole (SMX),
       Sulfisoxazole, Triple Sulfas

     Clinical Use
         Wide variety of uses.
         Triple sulfas or SMX for simple UTI.
Sulfonamides – Sulfamethoxazole (SMX),
       Sulfisoxazole, Triple Sulfas

     Toxicity
         Hypersensitivity reactions – rashes, eosinophilia, fever.
         Hemolysis.
             Blood cells use reduced glutathione to inactivate peroxides and
              oxygen radicals.
             Sulfonamides deplete the pool of reduced glutathione.
             In normal cells, the pool is replenished though NADPH
              generated when Glc-6-P is converted to 6-phosphogluconate
              by the dehydrogenase.
             Cells deficient in the enzyme are susceptible to peroxide and
              radical-induced hemolysis.
         Kernictus
             Bilirubin will be displaced by sulfonamides from its serum
              protein binding sites.
             The free bilirubin can then pass the blood-brain barrier of
              newborns and become deposited in the basal ganglia or
              subthalamic nuclei of the brain.
Trimethoprim

    Mechanism of Action
        Bacteriostatic.
        Inhibits DHFR.
Trimethoprim

    Clinical Use
        Extremely broad antibacterial spectrum,
         covering most gram-positive and gram-
         negative organisms.
        Often used in conjunction with Sulfonamides
         for synergistic effect.
Trimethoprim

    Toxicity
        Can result in megaloblastic anemia,
         leucopenia, and granulocytopenia.
            Can be reversed by administering folinic acid
             (leucovorin, citrovorum).
            Folinic acid bypasses the trimethoprim block in the
             cells of the bone marrow by conversion to the one-
             carbon cofactor 5-methyltetrahydrofolate.
Fluoroquinolones

    Mechanism of Action
        Bactericidal.
        Inhibits DNA topoisomerase II, which is
         involved in the unwinding of DNA to allow it
         wrap around histones for condensation.
Fluoroquinolones

    Clinical Use
        The fluorine group increases activity against
         gram-positive organisms while other
         structural changes facilitate entry into gram-
         negative organisms.
        Anaerobes usually resistant.
        Main use is against gram-negative rods of
         the urinary and gastrointestinal tracts, such
         as Pseudomonas.
Fluoroquinolones

    Toxicity
        Many.
Metronidazole

    Mechanism of Action
        Bactericidal.
        Forms toxic metabolites.
            The lipid solubility of the compound allows it to
             diffuse easily into microorganisms.
            In the cell, the 5’-NO2 group is reduced by the
             pyruvate:ferredoxin oxidoreductase system.
            During this reduction reaction, short-lived, highly
             reactive intermediates are formed that disrupt the
             organism’s DNA, causing strand breaks, helix
             destabilization, and unwinding.
Metronidazole

    Clinical Use
        Antiprotozoal – Giardia, Entamoeba,
         Trichomonas.
        Antibacterial – Bacteriodes, Clostridia.
        Part of triple therapy for the treatment of H.
         pylori.
Metronidazole

    Toxicity
        Present.
Polymyxins – Polymyxin B,
    Polymyxin E

    Mechanism of Action
        Bind to cell membranes of bacteria and
         disrupt their osmotic properties.
Polymyxins – Polymyxin B,
    Polymyxin E

    Clinical Use
        Resistant gram-negative infections.
        Especially useful against enteric, aerobic
         gram-negative bacilli, such as E. coli,
         Klebsiella, and Pseudomonas.
Polymyxins – Polymyxin B,
    Polymyxin E

    Toxicity
        Neurotoxicity includes paresthesias,
         dizziness, and ataxia.
Antituberculosis Drugs

     First Line Drugs
         Combine the greatest level of efficacy with
          an acceptable degree of toxicity.
             Rifampin
             Ethambutol
             Streptomycin
             Pyrazinamide
             Isoniazid (INH)
Antituberculosis Drugs

     Second Line Drugs
         Reserved for use when the bacilli exhibit or
          are expected to enhibit multiple resistance to
          the first line drugs or when one or more first
          line drugs are contraindicated.
             Cycloserine
             Many others
Isoniazid (INH)

     Mechanism of Action
         Highly selective for mycobacteria.
         Inhibits synthesis of mycolic acids, which are
          unique constituents of mycobacterial cell
          walls.
Isoniazid (INH)

     Clinical Use
         Tuberculosis.
         Only agent used alone for prophylaxis
          against tuberculosis.
Isoniazid (INH)

     Toxicity
         Neurotoxicity.
             Results from the hydrazine portion of isoniazid
              interacting with pyridoxalphosphate, inactivating
              the coenzyme.
             PLP is a cofactor of many enzymatic reactions in
              the body as it is the active form of Vitamin B6.
             The neurotoxicity can be prevented or treated with
              pyridoxine (B6) administration.
Rifampin

    Mechanism of Action
        Inhibits DNA-dependent RNA polymerase,
         thus preventing RNA synthesis.
    Clinical Use
        Tuberculosis.
        Others; usage against tuberculosis most
         common by far.
    Toxicity
        Yes, of course.
Resistance Mechanisms for
    Various Antibiotics

   Mechanisms used by bacteria against
    antibiotics.
Nonsurgical Antimicrobial
    Prophylaxis

   What we use when a patient is at risk
    of developing or contracting a certain
    condition.
Done!

								
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