Ch20 Antimicrobials and Chemotherapy
Pharmakeutikos
The practice of utilizing antimicrobial substances in medicine.
Introduction
Overview of the history and development of antimicrobials.
Spoken Too Soon: 1969, William Stewart (U.S. Surgeon General) and pharmaceutical companies:
Belief in having "closed the book on infectious disease".
Early 1900s: Infectious diseases were the leading cause of death in the U.S.
21st Century: Only 3 infectious diseases rank in the top ten causes of death in the U.S.
The "Magic Bullet" Concept
Pioneered by Paul Ehrlich's work on syphilis.
Emphasizes the ideal of an antimicrobial that targets pathogens without harming host cells.
Characteristics of the Ideal Antimicrobial Drug (Table 12.1)
Selectivity:
Selectively toxic to microbes but non-toxic to host cells.
Microbicidal Activity:
Microbicidal (kills microbes) rather than microbistatic (only inhibits growth).
Solubility:
Relatively soluble and effective even at high dilutions in body fluids.
Potency:
Remains potent long enough to act and is not prematurely broken down or excreted.
Resistance:
Not subject to the development of antimicrobial resistance.
Host Compatibility:
Complements the host's defenses, remains active in tissues.
Delivery:
Readily delivered to the site of infection.
Cost:
Not excessively expensive.
Safety:
Does not cause allergies or predispose the host to other infections.
Selectively Toxic
Definition of selectively toxic:
Low toxicity to vertebrate cells while effectively killing or inhibiting microbial cells.
Major goal of antimicrobials is to ensure selectivity; otherwise, potential harm to human cells may result.
Historical Context: Discovery of Antimicrobials
Sir Alexander Fleming (1928):
Notable discovery of the antibacterial properties of penicillin via contamination of S. aureus by mold.
This serendipitous contamination led to significant advancements in antimicrobial treatments.
Sources of Antimicrobials
Many antimicrobials originate from nature, particularly from fungi and bacteria:
Important Genera:
Streptomyces: Known for its production of various antibiotics.
Bacillus: Another key source.
Penicillium & Cephalosporium: Source of penicillin and cephalosporins respectively.
Table 20.1: Representative Sources of Antibiotics:
Microorganisms and Corresponding Antibiotics:
Gram-Positive Rods:
Bacillus subtilis → Compounds like Bacitracin.
Paenibacillus polymyxa
Actinomycetes:
Streptomyces spp. → Include Streptomyces griseus (Penicillin) and Streptomyces venezuelae.
Fungi:
Penicillium chrysogenum → Penicillin.
Cephalosporium → Cephalosporins.
Mechanisms of Action of Antimicrobials
Activity Spectrum
Narrow Spectrum:
Limited effectiveness, e.g., effective against gram-positive bacteria only.
Broad Spectrum:
Widespread effectiveness, e.g., effective against both gram-positive and gram-negative bacteria.
Concept Check
Antimicrobials effective against a wide variety of microbial types are termed (answer: broad-spectrum antimicrobials).
Important characteristics of antimicrobial drugs include:
A. Readily delivered to the site of infection.
B. High toxicity against microbial cells.
C. Do not cause serious side effects in humans.
D. Remains active in body tissues and fluids.
E. All of the choices are correct.
Expert Analysis of Antibiotics
Group activity: Analyze different groups of antibiotics, focusing on:
Mechanism of action
Effectiveness reasoning
Group assignments:
Group 1: Penicillin
Group 2: Rifampin (a rifamycin)
Group 3: Sulfonamides (TMP-SMZ)
Group 4: Polymyxins vs. Amphotericin B
Group 5: Tetracycline
Antibacterial Modes of Action
Different Targets of Antimicrobials
Cell Wall:
Block synthesis or repair of the cell wall.
Example: Penicillins and cephalosporins inhibit peptidoglycan cross-linking.
Nucleic Acid Structure & Function:
Interference in DNA/RNA formation.
Protein Synthesis:
Stopping protein synthesis.
Membrane Disruption:
Disruption of membranes leading to leakage.
Metabolic Pathway Disruption:
Affecting processes like folic acid synthesis.
Antibiotics Affecting Cell Walls
Mechanism:
Block synthesis or repair of cell wall, crucial for bacterial growth.
Examples:
Penicillins, Cephalosporins, etc.: Interfere with peptidoglycan cross-linking.
Why don’t penicillins affect human cells?
Human cells lack a cell wall and are not affected.
Consequences of Cell Wall Inhibition
Cell Lysis:
Resulting from exposing actively growing cells to antibiotics preventing cell wall synthesis.
This class of drugs is typically well tolerated with minimal toxicity.
Metabolic Disruption by Antimicrobials
Folic acid is a necessary precursor for amino acid and nucleic acid production.
Many drugs, particularly sulfa drugs, competitively inhibit enzymes critical for folic acid synthesis:
Example: Sulfonamides, which act as metabolic analogs resembling the normal substrate (PABA).
Translation Inhibition by Antimicrobials
Importance of targeting bacterial ribosomes:
An effective method due to differences from eukaryotic ribosomes.
Various ways drugs may interrupt ribosomal functions.
Cell Membrane Targeting Agents
Polymyxins
Specific Target: Outer membrane of Gram-negative bacteria.
Consequence: Membrane leakage, which can lead to cell death.
Potential Issues:
If the drug targets eukaryotic membranes, it could harm human cells as well.
Amphotericin B: A polyene that targets fungal cell membranes repeatedly.
DNA/RNA Inhibition
Mechanism:
Inhibition of bacterial RNA polymerase by certain drugs.
Example: Rifampin is effective against tuberculosis.
Classifications of Antimicrobials
There are about 20 different families of drugs:
Antibacterial: These are targeted specifically at bacteria.
Synthetic Antibacterials: Chemically synthesized drugs for bacterial infections.
Antifungal: Target fungal infections.
Antiprotozoan: Target protozoan infections.
Antihelminthic: Affect helminthic (worm) infections.
Antiviral: Used against viral infections.
Summary of Drug Classification and Usage
Most antimicrobials are primarily antibacterial agents; however:
Fewer drugs are effective against non-bacterial microbes due to their complexity and varied life cycles.
Drug resistance can develop at any stage.
Some drugs may result in significant side effects, e.g., kidney damage from aminoglycosides.
Antiviral treatments are complex due to viral replication within host cells.
Antiprotozoan Drugs
Quinine:
One of the original antimicrobials isolated from the bark of the cinchona tree. Introduced in Europe in the 1640s as a treatment for malaria.
Chloroquine:
Synthetic derivative of quinine; currently in use due to its efficacy.
Drug Resistance Mechanisms
Understanding Drug Resistance
Concept: Drug resistance is an outcome of bacterial evolution and adaptation, driven by rapid generation times and genetic variability.
Resistance can arise through:
Random spontaneous chromosomal mutations.
Bacterial genetic recombination.
Mechanisms of Acquired Resistance
Key Mechanisms:
Blocking entry of the drug into the cell.
Inactivation of the drug via enzymatic modification.
Alteration of the drug's target molecule (e.g. ribosomes).
Efflux mechanisms that pump drugs out of the bacterial cell.
Examples include enzymes that modify or degrade the antibiotic.
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Examples of Resistance Factors (R-Factors)
Four main mechanisms are significant in microbial resistance:
Blocking entry: Ensures drugs cannot enter the cell.
Inactivation by enzymes: Modifies the drug's structure chemically.
Alteration of target sites: Changes receptor structures within bacterial cells to prevent drug binding.
Efflux pumps: Remove drugs from within the cells before they can exert their effects.
Host & Drug Reactions
Host Toxicity and Organ Damage
Toxicity:
Many organs, especially the liver and kidney, can be affected by drug toxicity.
Allergic Responses:
Occurs when the immune system responds to drugs as if they were antigens.
Repeated exposures can lead to severe immune responses.
Disruption of Microflora
Indicates how the normal populations of bacteria (microflora) can be suppressed by antimicrobials.
Consequence: Superinfection can occur if resistant pathogens flourish post-treatment.
Drug Selection Considerations
Selecting a drug requires:
Identifying the causative pathogen.
Assessing sensitivity to specific drugs.
Considering the patient's medical condition.