Antibiotic

Aka: Antibiotic, Anti-Bacterial Agent, Antibacterial Agent, Minimum Inhibitory Concentration, Minimum Bactericidal Concentration, Bacteriostatic Antibiotic, Bacteriocidal Antibiotic, Beta Lactam, Anti-Ribosomal Antibiotic, Protein Synthesis Inhibitor Antibiotic, Anti-Metabolite Antibiotic, DNA-Inhibitor Antibiotic

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II. Definitions

  1. Antibiotic
    1. Substances that selectively kill or inhibit Microorganisms
    2. Targets specific to Microbes include Bacterial cell walls, cell membrane, and 30S or 50S ribosomal subunits
    3. Most Antibiotics are either naturally produced by Microorganisms, or their synthetic derivatives
  2. Bacteriocidal Antibiotic
    1. Bacteriocidal Antibiotics kill Bacteria
  3. Bacteriostatic Antibiotic
    1. Bacteriostatic Antibiotics inhibit Bacterial proliferation and spread, but do not kill the Bacteria
    2. Often works in concert with the Immune System, which subsequently kills Bacteria
  4. Minimum Inhibitory Concentration (MIC)
    1. Minimum concentration of an Antibiotic in a culture medium that will suppress Bacterial growth
    2. MIC cutoffs vary by organism and by Antibiotic, and are typically categorized as susceptible, intermediate or resistant
    3. One drug's lower MIC values than another drug, does not imply greater efficacy
    4. (2024) Presc Lett 31(1): 2-3
  5. Minimum Bactericidal Concentration (MBC)
    1. Antibiotic concentration killing 99.9% of Bacterial inoculum (Microbes in culture)

III. Background

  1. Most Antibiotics have one of 3 mechanisms of activity
    1. Bacterial Cell Wall Inhibitors (Transpeptidase inhibitors)
      1. Beta Lactams (e.g. Cephalosporins, Penicillins, Carbapenems)
    2. DNA Inhibitors (Antimetabolite Antibiotics)
      1. Fluoroquinolone
      2. Sulfonamides (Inhibit DNA, as well as RNA and Protein synthesis)
      3. Other DNA Inhibitors (Metronidazole, Nitrofurantoin, Rifampin)
    3. Protein Synthesis Inhibitors (Anti-Ribosomal Antibiotic at 30s or 50s ribosome)
      1. Macrolides
      2. Tetracyclines (e.g. Doxycycline)
      3. Aminoglycosides (e.g. Gentamicin)
      4. Other Protein Synthesis Inhibitors (Chloramphenicol, Linezolid, Clindamycin)
      5. Bacteriostatic activity against Gram Positives, Gram Negatives and Anaerobic Bacteria

IV. Mechanism: Bacterial Cell Wall Inhibitors (Beta Lactams)

  1. General: Beta Lactam
    1. Beta Lactam Structure
      1. Penicillins, Cephalosporins, Carbapenems and Monobactams are all Beta Lactams
      2. Beta Lactams share a 4-membered ring structure (3 Carbons, 1 Nitrogen), a type of cyclic amide
    2. Bacteria (Gram Positive and negative) have cell walls that contain peptidoglycans
      1. Peptidoglycans are repeated Disaccharides cross-linked with Amino Acids
      2. Transpeptidase cross-links peptidoglycan mesh in the synthesis of the Bacterial cell wall
    3. Beta Lactams bind and inactivate Transpeptidase (also known as Penicillin Binding Protein)
      1. Transpeptidase enzymes are located on the Bacteria's inner cytoplasmic membrane
      2. Beta Lactams must traverse outer cell wall layers to bind Transpeptidase
      3. Beta-Lactam's inhibition of Transpeptidase results in lysis and death of the Bacterial cell
    4. Beta-Lactams are inactivated by the enzyme Beta-Lactamase (Penicillinase)
      1. Beta-Lactamase is produced by beta-lactam resistant Bacteria
      2. Beta Lactamase cleaves a carbon-nitrogen bond in the 4 member Beta Lactam ring
    5. Other Beta Lactam Resistance Mechanisms
      1. Altered Transpeptidase Structure
        1. Prevents binding by Beta Lactams
        2. Example: Methicillin Resistant Staphylococcus Aureus (MRSA)
      2. Gram Negative Bacteria are protected by an additional lipid bilayer
        1. Molecules pass through this layer via porin channels (e.g. OmpF, OmpC) to access the cell wall
        2. Porin channels retrict larger molecules, and not all Beta Lactams can pass through porins
        3. Other Gram Negative Bacteria may down regulate porin channels to limit entry
      3. Beta Lactam Efflux Pumps
        1. Some Bacteria are able to actively pump the Beta Lactam out before transpeptidase binding
        2. Examples: E. coli (AcrAB-TolC) and Pseudomonas Aeruginosa (MexAB-OprM)
    6. Beta-Lactamase inhibitors have been developed to counter Beta Lactam resistance
      1. Amoxicillin-clavulanic acid (Augmentin)
      2. Ampicillin-Sulbactam (Unasyn)
      3. Ceftazidime-Avibactam
  2. Penicillins
    1. Natural Penicillins (e.g. Penicillin V) and semisynthetic Penicillins (e.g. Benzathine Penicillin)
      1. Cover Streptococci and Anaerobes
    2. Penicillinase-Resistant Semisynthetic Penicillin (e.g. Dicloxacillin, Nafcillin)
      1. Cover streptococci and MSSA (Methicillin-Sensitive Staphylococcus Aureus)
    3. Aminopenicillins (e.g. Amoxicillin, Augmentin)
      1. Cover streptococci and Gram Negative Bacteria
    4. Extended Spectrum Penicillin (e.g. Piperacillin Tazobactam)
      1. Cover streptococci, Gram Negatives and Pseudomonas
  3. Cephalosporins
    1. First Generation Cephalosporins (Cephalexin, Cefazolin)
      1. Covers Gram Positive Cocci (Streptococcus and MSSA), EKP Gram Negative Bacteria
    2. Second Generation Broad-spectrum Cephalosporins (e.g. Cefuroxime )
      1. Covers Gram Positive Cocci, EKP Gram Negative Bacteria, Haemophilus Influenzae
    3. Second Generation Anti-anaerobe Cephalosporins (e.g. Cefotetan, Cefoxitin)
      1. Covers Gram Positives, Gram Negatives, Bacteroides fragilis
    4. Third Generation Broad-Spectrum Cephalosporins (e.g. Ceftriaxone, Cefixime, Cefdinir)
      1. Covers Gram Positive Cocci, EKP and ESP Gram Negative Bacteria
    5. Third Generation Anti-Pseudomonal Cephalosporins (e.g. Ceftazidime)
      1. Covers EKP and ESP Gram Negative Bacteria, Pseudomonas
      2. Poor Gram Positive Cocci coverage, and no Coccobacilli coverage
    6. Fourth Generation Cephalosporins (e.g. Cefepime)
      1. Adds to broad spectrum third generation (broad spectrum Gram-positive and Gram-negative organisms)
      2. Additionally covers Beta-Lactamase resistant organisms and Pseudomonas
    7. Fifth Generation Cephalosporins (e.g. Ceftaroline)
      1. Adds to broad spectrum third generation (broad spectrum Gram-positive and Gram-negative organisms)
      2. Covers Pseudomonas and MRSA (Methicillin Resistant Staphylococcus Aureus)
  4. Other Beta Lactam Bacterial Cell Wall Inhibitors
    1. Carbapenems (e.g. Meropenem, Ertapenem)
      1. Cover Gram Positive Bacteria, Gram Negative Bacteria and Anaerobic Bacteria
    2. Monolactams (e.g. Aztreonam)
      1. Cover Gram Negative aerobic Bacteriaa
  5. Non-Beta Lactam Bacterial Cell Wall Inhibitors
    1. Lipopeptides (e.g. Daptomycin)
      1. Covers MRSA, Streptococcal Species, Vancomycin Sensitive Enterococcus

V. Mechanism: DNA Inhibitors (Antimetabolite Antibiotics)

  1. Fluoroquinolone
    1. First Generation Quinolones (Nalidixic Acid)
      1. Gram Negative Rod efficacy (no Pseudomonas coverage)
    2. Second Generation Quinolones (e.g. Ciprofloxacin )
      1. Covers Aerobic Gram Negative Rods (including Pseudomonas), and some Gram Positive coverage
    3. Third Generation Quinolones (e.g. Levofloxacin)
      1. Covers Gram Negative Rods, with greater Gram Positive Cocci coverage
    4. Fourth Generation Quinolones (e.g. Trovafloxacin)
      1. Covers Gram Negative Rods, Gram Positive Cocci and Anaerobes
  2. Sulfonamides (Inhibit DNA, as well as RNA and Protein synthesis)
    1. Trimethoprim Sulfamethoxazole (Bactrim, Septra)
      1. Covers enteric Gram Negative Bacteria (Urinary Tract Infections) and some Gram Positive organisms
      2. Also used in PCP Pneumonia treatment and prophylaxis (AIDS) and MRSA Skin Infections
    2. Other Sulfonamides
      1. Sulfadiazine (Toxoplasmosis prophylaxis)
      2. Sulfisoxazole (UTI prophylaxis)
  3. Other DNA Inhibitors
    1. Metronidazole
      1. Covers Anaerobes (e.g. Bacteroides, Peptococcus, Clostridioides difficile)
    2. Nitrofurantoin
      1. Covers many urinary pathogens (but NOT Pseudomonas, Klebsiella, Proteus Serratia or Acinetobacter)
    3. Rifamycin (e.g. Rifampin)
      1. Covers Mycobacterium (esp. Tuberculosis as part of multi-drug regimen)

VI. Mechanism: Protein Synthesis Inhibitors (Anti-Ribosomal Antibiotic at 30s or 50s ribosome)

  1. Background
    1. Antibiotics that inhibit Bacterial ribosomal activity prevent Protein synthesis and result in cell death
    2. Bacterial ribosomes differ from human ribosomes allowing for selective Antibiotic activity
      1. Humans have an 80S ribosome
      2. Bacteria have a 2 subunit ribosome (50S and 30S)
    3. Anti-Ribosomal Antibiotics target one of the two ribosome subunits
      1. Subunit 50S is targeted by Macrolides, Tetracyclines, Clindamycin, Chloramphenicol and Linezolid
      2. Subunit 30S is targeted by Aminoglycosides
  2. Macrolides
    1. Erythromycin
      1. Covers Bacteria without cell walls (Mycoplasma, Legionella, Chlamydia)
      2. Covers Aerobic Bacteria, Gram Positive Aerobes, Gram Negative Aerobes (except Campylobacter, Pasteurella)
    2. Extended Spectrum Macrolides (e.g. Azithromycin, Clarithromycin)
      1. Coverage includes organisms covered by Erythromycin
      2. Cover Chlamydia Trachomatis, Non-tuberculous Mycobacteria, Helicobacter and some respiratory infections
    3. Fidaxomicin (Dificid)
      1. Narrow spectrum Antibiotic (C. difficile, Staphylococcus, Enterococcus)
      2. Minimal systemic absorption when taken orally
  3. Tetracyclines (e.g. Doxycycline, Minocycline, Tetracycline)
    1. Cover MRSA, Helicobacter Pylori, Tick-borne illness (e.g. Lyme Disease), STDs (e.g. Chlamydia Trachomatis)
  4. Aminoglycosides (e.g. Gentamicin, Tobramycin, Amikacin)
    1. Cover aerobic and facultative Gram Negative Rods (including Pseudomonas)
    2. NO anaerobic activity
  5. Other Protein Synthesis Inhibitors
    1. Chloramphenicol
      1. Bacteriostatic activity against Gram Positives, Gram Negatives and Anaerobic Bacteria
    2. Linezolid
      1. Bacteriostatic against VRE, MRSA and bactertiocidal against Streptococcus species
    3. Clindamycin
      1. Covers Anaerobes and Gram Positive Bacteria (including MRSA coverage, but with high risk of resistance)
    4. Spectinomycin (Trobicin)
      1. Non-Aminoglycoside (despite suffix) with activity at the 50S ribosome
      2. Discontinued for U.S. human use in 2006 (but still used in U.S. veterinary medicine)
      3. Previously used to treat NeisseriaGonorrheae

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