Antimicrobial Drugs Notes

The History of Chemotherapy

  • Paul Ehrlich's Contribution: Credited for the birth of chemotherapy in early 20th century Germany.

    • Speculated about a 'magic bullet' to selectively destroy pathogens without harming the host.

    • Introduced the concept of selective toxicity.

    • Coined the term chemotherapy.

Key Concepts in Chemotherapy

  • Selective Toxicity: Ability to selectively find and destroy pathogens without damaging the host.

  • Chemotherapy: The use of chemicals to treat diseases.

Discovery of Antibiotics

  • Alexander Fleming (1928):

    • Discovered that the bacterium Staphylococcus aureus was inhibited by a mold (Penicillium notatum).

    • This led to the isolation of penicillin, the first antibiotic.

    • Introduced the term antibiosis, referring to substances produced by microorganisms to inhibit others.

    • Distinguishes between synthetic antimicrobial drugs and semisynthetic drugs (chemically modified in labs).

Antibiotic Development and Resistance

  • Antibiotics are easy to discover, but few hold medical or commercial value due to the rising problem of antibiotic resistance.

Sources of Antibiotics

  • Gram-Positive Rods:

    • Bacillus subtilis - Bacitracin

    • Paenibacillus polymyxa - Polymyxin

    • Over half produced by the genus Streptomyces which includes:

    • Streptomyces aureofaciens - Chloramphenicol

    • Fungi:

    • Penicillium chrysogenum - Penicillin.

Spectrum of Activity

  • Narrow Spectrum: Targets a specific group of microbes (either Gram-positive or Gram-negative).

  • Broad-Spectrum: Targets a wide variety of microbes (both Gram-positive and Gram-negative).

Classification of Antimicrobials

  • Bacteriostatic (inhibit growth) vs. Bactericidal (kill bacteria).

  • Examples of Bacteriostatic:

    • Chloramphenicol, Erythromycin, Clindamycin.

  • Examples of Bactericidal:

    • Aminoglycosides, Beta-lactams, Vancomycin.

Mechanisms of Action for Antibiotics

  1. Inhibition of Cell Wall Synthesis:

    • Penicillins, Cephalosporins, Bacitracin, Vancomycin.

  2. Inhibition of Protein Synthesis:

    • Chloramphenicol, Erythromycin, Tetracyclines, Streptomycin.

  3. Inhibition of Nucleic Acid Replication and Transcription:

    • Quinolones, Rifampin.

  4. Injury to Plasma Membrane:

    • Polymyxin B.

  5. Inhibition of Essential Metabolite Synthesis:

    • Sulfanilamide, Trimethoprim.

Cell Wall Synthesis Inhibitors

  • Penicillins: Group of over 50 antibiotics with a common β-lactam ring.

    • Natural: Extracted from Penicillium; examples include Penicillin G (injection) and Penicillin V (oral).

    • Disadvantages: Narrow activity spectrum; susceptible to penicillinases (β-lactamases).

Resistance to Penicillins

  • Penicillinases: Enzymes that cleave the β-lactam ring, leading to resistance, particularly in Staphylococcus aureus.

Semisynthetic Penicillins

  • Developed to overcome natural penicillin limitations.

  • Oxacillin: Narrow spectrum, resistant to penicillinase.

  • Aminopenicillins: Extended spectrum, effective against Gram-negatives.

  • Penicillins + β-lactamase inhibitors: Example - Amoxicillin + Clavulanic Acid = Augmentin.

Carbapenems and Cephalosporins

  • Carbapenems: Broad spectrum, often reserved for severe infections.

  • Cephalosporins: Grouped by development generation, effective against Gram-positive and some Gram-negative bacteria.

Protein Synthesis Inhibitors

  • Chloramphenicol: Binds to the 50S ribosome, inhibiting peptide bond formation; can cause bone marrow suppression.

  • Aminoglycosides: Change the shape of the 30S subunit, can cause side effects like auditory damage.

  • Tetracyclines: Broad-spectrum antibiotics, risk of suppressing beneficial intestinal microbiota.

Nucleic Acid Synthesis Inhibitors

  • Rifampin: Important in treating tuberculosis; penetrates tissues effectively.

  • Quinolones: Inhibit DNA gyrase, examples include Ciprofloxacin.

Antifungal and Antiviral Drugs

  • Antifungal Treatments: Focused on targeting ergosterol in fungal plasma membranes.

    • Examples include Nystatin and Amphotericin B.

  • Antiviral Drugs: Focus on inhibiting viral entry, nucleic acid synthesis, and maturation processes.

Drug Testing and Susceptibility

  • Kirby-Bauer Test: Measures zones of inhibition to evaluate antibiotic effectiveness.

  • Minimum Inhibitory Concentration (MIC): Smallest effective dose correlating with the size of inhibition zones.

Therapeutic Index

  • Definition: Ratio of the toxic dose to the effective dose; a larger therapeutic index indicates a safer drug.

    • Example Calculation:

    • Drug X: TD50 = 18ug/ul, ED50 = 10ug/ul -> TI = 1.8

    • Drug Y: TD50 = 23ug/ul, ED50 = 21ug/ul -> TI = 1.095

    • Drug Z: TD50 = 15ug/ul, ED50 = 2ug/ul -> TI = 7.5

Community Acquired Pneumonia (CAP)

  • Empiric Treatment examples based on patient type and comorbidities.

    • Treatment includes macrolides or respiratory fluoroquinolones based on resistance patterns.