In-Depth Notes on Antimicrobial Medications

Chapter 20: Antimicrobial Medications

A Glimpse of History

• Paul Ehrlich (1854-1915):

  • Degree in medicine.

  • Observed that certain dyes can stain bacterial cells but not animal cells, highlighting fundamental differences between cell types.

  • Searched for a “magic bullet” to selectively kill microbes without harming humans.

  • Synthesized arsenic compounds for syphilis treatment, notably Salvarsan (arsphenamine), effective in 1910 against Treponema pallidum (causes syphilis).

20.1 History and Development of Antimicrobial Drugs

• Discovery of Antimicrobial Drugs:

  • Salvarsan (1910): First documented antimicrobial drug from Paul Ehrlich.

  • Prontosil (1932): Discovered by Gerhard Domagk, treated streptococcal infections; the active compound was sulfanilamide.

  • Both compounds are chemotherapeutic agents, chemicals used to treat diseases.

• Discovery of Antibiotics:

  • Penicillin (1928): Discovered by Alexander Fleming from the mold Penicillium, showed effectiveness against Staphylococcus.

  • Unable to purify, research was resumed by Ernst Chain and Howard Florey in 1941, leading to successful treatment.

  • WWII accelerated research, leading to the proliferation of various antibiotics, including penicillin G.

• Further discoveries:

  • Streptomycin (1943) was purified by Selman Waksman from Streptomyces griseus.

20.2 Features of Antimicrobial Drugs

• Selective Toxicity:

  • Antimicrobials should cause greater harm to microbes than to human cells.

  • Toxicity is estimated by therapeutic index: TI = rac{(Lowest dose toxic to patient)}{(Dose used for therapy)}.

  • Example: Penicillin G targets bacterial cell wall, absent in humans.

• Antimicrobial Action:

  • Bacteriostatic drugs: Inhibit bacterial growth; patient’s immune system must eliminate the bacteria.

  • Bactericidal drugs: Kill bacteria directly.

• Spectrum of Activity:

  • Broad-spectrum: Affects a wide range of bacteria, useful for immediate treatment in life-threatening conditions.

  • Narrow-spectrum: Targets specific bacteria; minimal disruption of normal microbiota.

• Effects of Drug Combinations:

  • Antagonistic (interfere with each other), synergistic (enhance each other), or additive effects.

• Tissue Distribution, Metabolism, and Excretion:

  • Different drugs have varied behaviors in the body regarding their distribution and metabolic processes (e.g., some cross the blood-brain barrier).

• Adverse Effects:

  • Include allergic reactions and toxic effects; can disturb normal microbiota, allowing pathogens to thrive (e.g., Clostridium difficile).

• Resistance to Antimicrobials:

  • Innate resistance (e.g., lack of target mechanisms) and acquired resistance through mutations or horizontal gene transfer.

20.3 Mechanisms of Action of Antibacterial Drugs

• Antibacterial drugs target specific processes in bacteria:

  • Cell wall synthesis: Inhibitors include eta-lactam drugs (e.g., penicillin).

  • Protein synthesis: Affected by drugs like aminoglycosides, tetracyclines, and macrolides.

  • Nucleic acid synthesis: Inhibited by fluoroquinolones and rifamycins.

  • Metabolic pathways: Sulfonamides and trimethoprim inhibit folate synthesis.

  • Cell membrane integrity: Drugs like polymyxin B disrupt the membrane.

• Specific Drug Classes:

  • eta-lactam drugs: Include penicillins (e.g., penicillin G) and cephalosporins.

  • Aminoglycosides: Bactericidal, bind to 30S subunit of ribosome affecting translation.

  • Tetracyclines: Bacteriostatic, block tRNA attachment at 30S subunit.

20.4 Determining Susceptibility of Bacterial Strains

• Minimum Inhibitory Concentration (MIC):

  • Lowest concentration preventing bacterial growth.

  • Minimum Bactericidal Concentration (MBC): Lowest concentration killing 99.9% of bacterial cells.

  • Techniques like disc diffusion tests (Kirby-Bauer) are commonly used to assess susceptibility.

20.5 Resistance to Antimicrobial Drugs

• Increasing Resistance:

  • Overuse and misuse of antibiotics have led to a significant rise in resistant strains (e.g., 90% of Staphylococcus aureus resistant to penicillin).

• Mechanisms of Acquired Resistance:

  • Drug-inactivating enzymes, alteration of target sites, decreased uptake, and increased drug elimination (efflux pumps) contribute to resistance.

• Acquisition of Resistance Factors:

  • Can arise from spontaneous mutations or through gene transfer, often via plasmids.

  • Examples include MRSA (methicillin-resistant Staphylococcus aureus) and vancomycin-resistant enterococci (VRE).

20.6 Mechanisms of Action of Antiviral Drugs

• Targeting Viral Mechanisms:

  • Viruses require host machinery for replication, thus limiting drug targets.

  • Classifications of antiviral drugs include entry inhibitors, nucleic acid synthesis inhibitors, and protease inhibitors.

• Key Drugs:

  • Entry inhibitors: e.g., Enfuvirtide for HIV.

  • Nucleoside analogs: e.g., Acyclovir for herpes viruses.

  • Protease inhibitors: e.g., Ritonavir for HIV.

20.7 Mechanisms of Action of Antifungal Drugs

• Fungal Drug Categories:

  • Plasma Membrane Disruption: Polyenes (Amphotericin B) and azoles target ergosterol in fungal membranes.

  • Cell Wall Synthesis Inhibition: Echinocandins target ẞ-1,3 glucan synthesis.

  • Nucleic Acid Synthesis Inhibition: Flucytosine interferes with nucleic acid production in fungi.

• Important Considerations:

  • Toxicity, breadth of activity, and resistance development are critical in antifungal therapy.

1. The first successful antimicrobial agent is Salvarsan, discovered by Paul Ehrlich.

2. The first antibiotic discovered is Penicillin, which was discovered by Alexander Fleming.

3. Definitions:

   • Chemotherapeutic agent: Chemicals used to treat diseases.

   • Antimicrobial drug or agent: Substances that kill or inhibit the growth of microorganisms.

   • Semisynthetic: Derivatives of naturally occurring antibiotics modified in the laboratory to enhance effectiveness.

   • Antibiotic: A type of antimicrobial drug that specifically targets bacteria.

   • Selective toxicity: The ability of a drug to harm microbes without causing significant harm to the host organism.

   • Bacteriostatic: Drugs that inhibit bacterial growth, relying on the immune system to eliminate the bacteria.

   • Bactericidal: Drugs that kill bacteria directly.

4. Key factors in selecting an antimicrobial agent:

   • Selective toxicity: Importance of targeting microbes without harming human cells.

   • Spectrum of activity: Broad-spectrum affects many bacteria; narrow-spectrum targets specific bacteria.

   • Tissue distribution: The drug's ability to reach the site of infection.

   • Metabolism and excretion of the drug: How the drug is processed and eliminated from the body.

   • Adverse effects: Potential side effects on the patient.

   • Synergistic combinations: When combined drugs enhance each other's effectiveness.

   • Microbial resistance: The ability of microbes to resist the effects of drugs.

5. Broad-spectrum antimicrobials affect a wide range of bacteria, while narrow-spectrum antimicrobials target specific bacteria, causing minimal disruption to normal microbiota.

6. Terms related to antimicrobial drug combinations:

   • Synergistic: Combinations that enhance each other's effects.

   • Antagonistic: Combinations that interfere with each other's effectiveness.

   • Additive: Combinations with effects that equal the sum of their individual effects.

7. Major types of adverse effects caused by antimicrobial agents:

   • Allergic reactions: Immune system responses to drugs.

   • Toxic effects: Harmful effects on human cells or organs.

   • Suppression of normal microbiota: Disruption of beneficial organisms, allowing opportunistic pathogens to thrive.

8. Microbial resistance is a major problem due to the overuse and misuse of antibiotics, leading to increased resistant strains, complicating treatment options.

9. Major antibacterial drugs by their modes of action:

   • Inhibition of cell wall synthesis: E.g., Beta-lactam drugs like penicillin.

   • Inhibition of protein synthesis: E.g., Aminoglycosides and tetracyclines.

   • Inhibition of nucleic acid synthesis: E.g., Fluoroquinolones.

   • Inhibition of metabolic pathways: E.g., Sulfonamides.

   • Interference with cell membrane function: E.g., Polymyxin B.

   • Interference with Mycobacterium tuberculosis metabolism: Specific drugs targeting tuberculosis.

10. Bacterial sensitivity to antibacterial agents can be determined using laboratory tests that measure the growth inhibition of bacteria in the presence of antibiotics.

11. Laboratory tests:

    • Determination of minimum inhibitory concentration (MIC): Lowest concentration preventing bacterial growth.

    • Determination of minimum bactericidal concentration (MBC): Lowest concentration killing 99.9% of bacterial cells.

    • Diffusion bioassay: Testing antibiotics on agar plates.

    • Kirby-Bauer disc diffusion: Technique using antibiotic-impregnated discs placed on agar plates to measure the zone of inhibition.

    • Standard curve correlation: Interpreting the relationship between zone size and antibiotic concentration in diffusion assay tests.

12. Major antifungal drugs by their modes of action:

    • Disruption or damage of cell membrane: E.g., Polyenes targeting ergosterol.

    • Inhibition of nucleic acid synthesis: E.g., Flucytosine affecting nucleic acid production in fungi.