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Antibiotics (Gram Bacterial (Classification Tool (Gram stain steps…

- - - - Application of crystal violet (purple dye)
      - Application of Iodine (mordant)
      - Alcohol wash (decolorization): remove dye from gram negative cells and dehydrates gram positive cell membranes
      - Application of safranin (counterstain): for gram negative bacteria
  - - - Gram Negative Bacteria
        
        Alcohol removes the thin peptiddoglycan layer from gram negative bacteria and dehydrates the membranes of gram positive bacteria, promoting crystal violet retention.
      - Gram Positive Bacteria
        
        A thick peptidoglycan layer which resists the decolorization by alcohol
- - - - Cell membrane
      - Folic acid metabolism
      - Cell wall synthesis
      - DNA replication
      - RNA synthesis
      - Protein synthesis
    - - Steps
        
        The peptidyl tRNA at the donor site, with amino acids 1 through 5, then binds the growing amino acid 6 (transpeptidation)
        
        the charged tRNA unit carrying amino acid 6 binds to the acceptor site on the 70s ribosome.
        
        The uncharged tRNA left at the donor site is released.
        
        The new 6-amino acid chain with its tRNA shifts to the peptidyl site (Translocation).
        
        Inhibit step 1: the tetracyclines (T) bind to the 30s subunit and prevent binding of the incoming charged tRNA unit.
        
        Inhibit step 2: Chloramphenicol (C) and macrolides (M) bind to the 50s subunit and block transpeptidation step.
- - - - Alter the intracellular target of the drug
      - The same kind of drug resistance mechanism can be specified by many different genes
      - Others target how the drug is transported
      - Some are directed at the antibiotic itself
      - More than one type of mechanism may provide resistance to the same antibiotic
  - - - A susceptible host in which an antibiotic is able to bind tightly to its specific target and exert an inhibitory effect.
        
        Modification of the target by addition of a chemical group can also prevent antibiotic binding without altering the primary protein sequence of the target, which retains its activity
        
        Mutation of the target site or recombination to provide a mosaic allele results in a functional target with reduced affinity for the antibiotic, which does not bind efficiently and therefore hasj a reduced or negligible effect
  - - - Mechanisms of ABR compared to MDR cancer
        
        Decreased influx, increased efflux, drug modification, target modification
        
        Cancer: DNA repair and blocked apoptosis, epigenetics, plasticity, heterogeneity
        
        As bacteria cells do not undergo classical apoptosis, they are not characterized as blocking apoptosis and other scripted cell death pathways
        
        Bacteria: mutational response and selection (cancer does this too)
        
        The shared mechanisms of drug resistance in cancer and bacteria are the same
- - - - Resistance, Tolerance, Persistance
        
        Susceptible VS tolerant bacterial strains: MIC for a tolerant strain of bacteria is similar to that of a susceptible strain; however, MDK for a tolerant strain is substantially higher than the MDK99 for a susceptible strain.
        
        Susceptible VS persistent bacterial strains: A persistent strain of bacteria has a similar MIC and a similar MDK99 to a susceptible strain; however, the MDK for 99.99% of bactrial cells in the population (MDK99.99) is substantially higher for a persistent strain than the MDK99.99 for a susceptible strain.
        
        Susceptible VS resistant bacterial strains: MIC for a strain of bacteria that is resistant to an antibiotic is substantially higher than the MIC for a susceptible strain.
    - - PK/PD Models
        
        T > MIC: time during which the serum concentration of antibiotic remains above the MIC
        
        PAE: Post-Antibiotic Effect. Antibiotics that correlate well with each parameter are also shown in respective areas.
        
        AUC/MIC: the ratio between the 24h area under the serum AUC and the MIC
        
        Cmax/MIC: ratio between the peak serum concentration of the antibiotic reached in the serum and the MIC
        
        Use to predict drug efficacy
    - - Importance
        
        Some ABs are bacteriostatic and efficacy is determined by maintaining an AUC greater than MIC.
        
        Some ABs are concentration-dependent: Cmax and AUC relative to MIC determine activity
        
        Penetration, bacterial density, barriers, interactions are different for different cases; PD cannot be measured for each patient. Tolerance and Persistence can lead to the selection of resistant strains even in the presence of non-time-dependent antimicrobials.
        
        Some ABs are time-dependent and have slow action: increase above maximum killing action (4*MIC) does not increase activity. shorter dosing interval increases time that concentration is above MIC
        
        Responses to many ABs are decreasing due to ABR
- - - - Plasmid aquisition of ABR
        
        Replication is independent of bacterial chromosome
        
        transferred across species and genera
        
        Many species, multiple drugs, high transfer rate (conjugation)
        
        Most clinically relevant mechanism of ABR aquisition
        
        another level of transfer added by transposons
        
        transposase repressor (synthesis)
        
        ABR gene
        
        transposase (excision and insertion)
        
        Can move from plasmid to plasmid or to bacterial chromosome
        
        ABR transposon = 3 genes (inverted repeated based on either end)
        
        R factors = Resistance plasmids
        
        2 sets of genes
        
        Drug resistance genes that encode the proteins that mediate drug resistance.
        
        resistance transfer genes that encode the sex pilus and other proteins that mediate transfer of the plasmid DNA during conjugation
      - Intrinsic resistance mechanisms
        
        Beta-lactam antibiotics targeting a PBP
        
        Antibiotic B can also enter the cell via a porin, but unlike A, it is efficiently removed by efflux.
        
        Antibiotic C cannot cross the outer membrane and so is unable to access the target PBP
        
        Antibiotic A can enter the cell via a membrane-spanning porin protein, reach its target and inhibit peptidoglycan synthesis.
      - Antibiotic resistance gene transfer paths
        
        Phage-mediated transduction
        
        Transposons
        
        Transformation by naked DNA that is released by dead cells
        
        Cell-to cell conjugation