Antimicrobial Drugs and Their Mechanisms

Sir Alexander Fleming

  • Discovered the bacteriolytic substance Lysozyme.
  • Found a halo of inhibition around Staphylococcus bacteria near a mold contaminant.

Discovery of Penicillin

  • Accidentally discovered by Alexander Fleming in 1928 when observing penicillin activity on a contaminated plate.
  • Initially, Fleming did not believe that penicillin could be developed further.
  • Effectiveness was later demonstrated by Florey, Chain, and Heatley in 1939.
  • Fleming, Florey, and Chain received the Nobel Prize in 1945 for their contributions.

General Characteristics of Antimicrobial Drugs

  • Selective Toxicity: The ability of a drug to kill or inhibit pathogen while damaging the host as little as possible.
  • Therapeutic Dose: The drug level required for effective clinical treatment.
  • Toxic Dose: The drug level at which the drug becomes too toxic for the patient, leading to side effects.
  • Therapeutic Index: The ratio of toxic dose to therapeutic dose determines the drug's safety.

Key Terms

  • Side Effects: Undesirable effects of drugs on host cells.
  • Narrow-Spectrum Drugs: Target only a few different pathogens.
  • Broad-Spectrum Drugs: Target a wide variety of pathogens.
  • Cidal Agents: Kill microbes.
  • Static Agents: Inhibit microbial growth.

Determining Antimicrobial Activity

  • Minimal Inhibitory Concentration (MIC): The lowest concentration of a drug that prevents the growth of a particular organism.
  • Minimal Lethal Concentration (MLC): The lowest concentration of a drug that kills the pathogen.
Dilution Susceptibility Test
  • Conducted by diluting the drug in regular intervals (usually doubling concentrations) in a Mueller-Hinton broth.
Kirby-Bauer Method
  • Fresh bacteria inoculated on a Mueller-Hinton plate, dried for 5 minutes, and antibiotic disks added for testing.
E-test
  • Similar to disk diffusion but utilizes a strip with a gradient of antibiotic concentration. The intersection of the elliptical zone of inhibition with the strip indicates MIC.

Antibiotics and Their Targets

  • Cell Wall Synthesis: Cycloserine, Vancomycin, Bacitracin, Penicillins, Cephalosporins, Monobactams, Carbapenems.
  • DNA Gyrase: Quinolones like Nalidixic acid and Ciprofloxacin.
  • Folic Acid Metabolism: Trimethoprim and Sulfonamides.
  • Cytoplasmic Membrane Function: Polymyxins and Daptomycin.
  • RNA Elongation: Actinomycin.
  • Ribosomes: Inhibitors like Erythromycin (macrolides), Chloramphenicol, Clindamycin, Tetracyclines, Gentamicin.

Antibiotic Resistance Patterns

  • Emergence of resistant strains such as Candida albicans, Acinetobacter spp., and Staphylococcus aureus among others.
  • Resistance trends observed from 1950 to 2015.

Prevention of Antimicrobial Drug Resistance

  • Vaccination to prevent common diseases.
  • Avoid unnecessary invasive procedures to reduce infection risk.
  • Identify and target pathogens accurately.
  • Use oldest effective antimicrobial drugs whenever applicable.
  • Monitor antimicrobial usage to track effectiveness and resistance.
  • Break the chain of contagion through good hygiene.
  • Consult with experts for tailored treatments.

Specific Antibiotics and Mechanisms

  • Penicillin: Contains a beta-lactam ring; derivatives include Methicillin and Ampicillin with various spectra of activity.
  • Cephalosporins: Originally isolated from cephalosporium, features a beta-lactam ring and has several generations.
  • Vancomycin: A glycopeptide antibiotic, works via binding to D-ala-D-ala and is considered a last-resort drug.

Resistance Mechanisms

  • Beta-lactamases: Enzymes produced by some bacteria to degrade beta-lactam antibiotics.
  • Clavulanic Acid: Inhibits beta-lactamases and is combined with amoxicillin as "Augmentin."
  • Avibactam: A novel non-beta-lactam beta-lactamase inhibitor effective against multi-drug resistant pathogens.

Antibiotics Acting on Protein Synthesis

  • Aminoglycosides: Bind to 30S ribosomal subunit, examples include Streptomycin and Kanamycin, resistance due to various mechanisms.
  • Tetracyclines: Feature a 4-ring structure and also bind to 30S subunit, resistance via efflux and ribosomal modification.
  • Macrolides: Large lactone rings like Erythromycin targeting 50S subunit.

Metabolic Inhibitors

  • Sulfonamides and Trimethoprim: Inhibit folic acid synthesis by mimicking PABA.

Nucleic Acid Synthesis Inhibitors

  • Quinolones: Inhibit DNA synthesis, including examples like Ciprofloxacin.