Ch_20_lecture

Chapter 20: Antimicrobial Medications

Introduction

• The concept of medicine emphasizes the importance of physicians taking care of their own health and well-being to practice effectively.

Page 1: Historical Context

• Proverb Reflection: "Physician, heal yourself" (Luke 4:23) suggests that medical practitioners must also care for themselves.

Page 2: A Glimpse of History

• Paul Ehrlich (1854–1915)

  • Degree in medicine.

  • Discovered that certain dyes could stain bacteria without affecting animal cells, indicating a fundamental difference in cell types.

  • Sought a "magic bullet" to target microbial pathogens selectively.

  • Salvarsan (606th compound):

    • Synthesized arsenic compounds for treating syphilis caused by Treponema pallidum.

    • Effective in laboratory animals, but toxicity was a concern.

    • Showed that some chemicals could selectivity kill microbes without harming human cells.

Page 3: Discovery of Antimicrobial Drugs

• Salvarsan: First documented antimicrobial compound developed by Ehrlich in 1910.

• Prontosil: Discovered by Gerhard Domagk in 1932 to treat streptococcal infections.

  • Indirectly led to the identification of sulfanilamide as the active compound required for effectiveness.

• Chemotherapeutic Agents: Chemicals used to treat diseases, collectively referred to as antimicrobials.

Page 4: Discovery of Antibiotics

• Penicillin: Discovered by Alexander Fleming in 1928 from Penicillium mold, effective against Staphylococcus.

  • Initially abandoned due to inability to purify it.

  • Purified by Ernst Chain and Howard Florey in 1941, showing dramatic clinical improvements.

• World War II: Accelerated research and development of penicillin.

Page 5: Further Discovery of Antibiotics

• Selman Waksman: Purified streptomycin from Streptomyces griseus.

  • Extensive screening of microbial strains for new antibiotics continues today.

• Development Trends: Structural alterations of penicillin led to new variants from the 1950s onwards, including methicillin and various derivatives.

Page 6: Key Features of Antimicrobial Drugs

• Selective Toxicity: Effectively harms microbes while sparing human cells.

  • Therapeutic index defined as the ratio of toxic dose to effective dose for treatment.

  • Example: Penicillin G targets bacterial cell wall synthesis, which human cells lack.

• Action of Antimicrobials:

  • Bacteriostatic: Inhibit growth; rely on the host's immune system to clear the infection.

  • Bactericidal: Kill bacteria directly.

Page 7: Spectrum of Activity

• Broad-Spectrum Antimicrobials: Affect a wide range of bacteria, useful in emergencies when pathogens are unidentified; however, they can disrupt normal microbiota.

• Narrow-Spectrum Antimicrobials: Target specific bacteria; require identification and sensitivity testing, causing minimal disruption to normal microbiota.

• Drug Interactions: Some drug combinations may be antagonistic, while others may be synergistic, thereby enhancing effectiveness.

Page 8: Drug Metabolism and Excretion

• Pharmacokinetics: Antimicrobial drugs behave differently based on tissue distribution, metabolism, and excretion pathways.

  • Some drugs are unstable in low pH, requiring injection.

  • Half-life determines dosage frequency, especially important for patients with organ dysfunction.

• Adverse Effects: Can include allergies, toxicity, and disruption of normal flora, allowing opportunistic infections like Clostridium difficile.

Page 9: Resistance to Antimicrobials

• Intrinsic Resistance: Some bacteria possess innate resistance due to structural characteristics (e.g., lack of cell walls in Mycoplasma).

• Acquired Resistance:

  • Resulting from mutations or horizontal gene transfer; contributes to the growing issue of antibiotic resistance among bacterial populations.

Page 10: Mechanisms of Action of Antibacterial Drugs

• Target Processes and Structures: Antibacterial drugs attack specific bacterial functions including:

  • Cell wall synthesis

  • Protein synthesis

  • Nucleic acid synthesis

  • Metabolic pathways

  • Cell membranes

Pages 11-13: Detailed Mechanisms

Targeting Cell Wall Synthesis

• β-Lactam Drugs: Including penicillins, inhibit penicillin-binding proteins involved in peptidoglycan synthesis, effective against actively growing bacteria.

• Resistance Mechanisms: Bacteria may produce β-lactamases that degrade these drugs, leading to treatment failures.

Targeting Protein Synthesis

• Various Classes:

  • Aminoglycosides, tetracyclines, macrolides, and others that interfere with the ribosomal functions essential for bacterial growth.

• Mechanisms of Resistance: Alterations in ribosomal RNA or enzyme production that modify the drug can lead to resistance outcomes.

Targeting Nucleic Acid Synthesis

• Fluoroquinolones: Block DNA synthesis by inhibiting topoisomerases.

• Rifamycins: Inhibit RNA polymerase, affecting transcription processes in bacterial cells.

Page 14-16: Classes of Antibacterial Drugs

• Cell Wall Synthesis Inhibitors: Include diverse groups of penicillins and other β-lactams with varying spectra against Gram-positive and Gram-negative bacteria. Penicillins can be modified to be resistant to penicillinase.

Page 17-19: Efficacies and Challenges

• Penicillins: Share a basic structure with variations improving efficacy against different bacterial strains, including resistant forms.

• Ongoing Development: Research continues to develop new agents and combinations to overcome resistance challenges.

Page 20-22: Viral and Fungal Treatments

Antiviral Drugs

• Anti-HIV agents, protease inhibitors, and non-nucleoside inhibitors target various stages of viral replication.

Antifungal Agents

• Drugs such as polyenes and azoles focus on the unique structures of fungal cells, disrupting their membranes and metabolic processes.

Page 23-49: Further Mechanisms in Antifungals, Resistance, and Susceptibility

Antifungal Strategies

• Diversified approaches targeting cell membrane and nucleic acid synthesis, highlighting specific drug classes.

Resistance Mechanisms

• Extensive discussions on the evolving nature of bacterial resistance, looking at genetic factors, resistance transfer, and examples of resistant strains (e.g., MRSA, VRE).

Conclusion: Antimicrobial Resistance and Prevention Strategies

• Global Concern: The rise of antimicrobial resistance requires action from healthcare professionals and patients alike. Proper education on the appropriate use of antimicrobials is critical as resistant organisms continue to spread.

1. First successful antimicrobial agent: Salvarsan, discovered by Paul Ehrlich.

2. First antibiotic discovered: Penicillin, discovered by Alexander Fleming.

3. Definitions:

   • Chemotherapeutic agent: Chemicals used to treat diseases, collectively referred to as antimicrobials.

   • Antimicrobial drug or agent: A substance that kills or inhibits the growth of microorganisms.

   • Semisynthetic: Modified natural compounds to improve efficacy or reduce toxicity.

   • Antibiotic: A type of antimicrobial agent specifically used to kill or inhibit the growth of bacteria.

   • Selective toxicity: The ability to kill or inhibit microbial pathogens without harming human cells.

   • Bacteriostatic: Agents that inhibit the growth of bacteria, allowing the host’s immune system to clear the infection.

   • Bactericidal: Agents that directly kill bacteria.

4. Key factors in selecting an antimicrobial agent:

   • Selective toxicity: Ensuring the drug harms microbes without affecting human cells.

   • Spectrum of activity: Determining if the drug affects a wide range or a specific range of pathogens.

   • Tissue distribution: Understanding how well the drug penetrates different body tissues.

   • Metabolism and excretion: Knowing how the drug is processed and eliminated from the body.

   • Adverse effects: Considering potential side effects or toxicity risks.

   • Synergistic combinations: Using drug pairs that enhance each other's effects.

   • Microbial resistance: Awareness of any existing resistance to the antimicrobial agent.

5. Broad-spectrum vs. narrow-spectrum antimicrobials:

   • Broad-spectrum antimicrobials: Affect a wide range of bacteria; useful when the pathogen is unknown but may disrupt normal microbiota.

   • Narrow-spectrum antimicrobials: Target specific bacteria, minimizing disruption to normal microbiota.

6. Antimicrobial drug combinations:

   • Synergistic: Combined effect is greater than the individual effects of the drugs.

   • Antagonistic: Combined effect is less effective than the individual effects.

   • Additive: Combined effect is equal to the sum of individual effects.

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

   • Allergic reactions: Hypersensitivity responses ranging from mild to severe.

   • Toxicity: Harm to organs or systems due to drug side effects.

   • Disruption of normal flora: Leading to opportunistic infections, like Clostridium difficile.

8. Microbial resistance to antimicrobial agents is a major problem because it leads to treatment failures, prolonged illness, higher medical costs, and increased mortality.

9. Major antibacterial drugs by mode of action:

   • Inhibition of cell wall synthesis: e.g., β-lactam drugs like penicillin.

   • Inhibition of protein synthesis: e.g., tetracyclines and macrolides.

   • Inhibition of nucleic acid synthesis: e.g., fluoroquinolones and rifamycins.

   • Inhibition of metabolic pathways: e.g., sulfanilamide.

   • Interference with cell membrane function: e.g., polymyxins.

   • Interference with Mycobacterium tuberculosis metabolism: e.g., isoniazid.

10. Determining bacterial sensitivity in the laboratory can be achieved through methods like disk diffusion and broth dilution tests to analyze how effectively an antimicrobial agent inhibits or kills a bacterial strain.

11. Laboratory tests:

• Minimum inhibitory concentration (MIC): The lowest concentration of drug that prevents bacterial growth.

• Minimum bactericidal concentration (MBC): The lowest concentration of drug that kills a certain percentage of bacteria.

• Diffusion bioassay: Evaluates sensitivity by measuring zones of inhibition around antimicrobial disks.

• Kirby-Bauer disc diffusion: A standardized test to determine the susceptibility of bacteria to antibiotics based on zone sizes. Understanding the standard curve allows interpretation of effectiveness of antibiotic concentration.

12. Major antifungal drugs by their modes of action:

• Disruption or damage of cell membrane: e.g., polyenes and azoles.

• Inhibition of nucleic acid synthesis: e.g., flucytosine.