Antimicrobial Drugs & Antibiotic Resistance

Misconceptions about Antibacterials and Viral Infections
- Example: Colds are viral.

History of Drug Discovery and Development
Clinical Considerations in Prescribing Antimicrobial Drugs
- Ideal antimicrobial agent
- Spectrum of action
- Effectiveness, safety and side effects
- Dosage and route of administration
Mechanisms of Antimicrobial Action
- Inhibition of:
  - Cell wall synthesis
  - Protein synthesis
  - Cytoplasmic membrane
  - Metabolic pathways
  - Nucleic acid synthesis
Mechanisms of Other Antimicrobial Drugs (targeting fungi, protozoans, viruses)
- Same points as above
Resistance to Antimicrobial Drugs
- Mechanisms of resistance and approaches to retard resistance

Paul Ehrlich & Sahachiro Hata:
- Developed “Magic bullets” that kill infectious microbes without harming the patient.
- Notable drug: Salvarsan 606
Alexander Fleming:
- Discovered natural antibiotic penicillin from the fungus Penicillium
Howard Florey & Ernst Chain:
- Achieved mass production of penicillin
Josef Klarer, Fritz Mietzsch, & Gerhard Domagk:
- Discovered the synthetic antimicrobial sulfanilamide
Dorothy Hodgkin:
- Determined the structure of penicillin; led to the development of semisynthetic antimicrobials
Selman Waksman:
- Discovered more natural antimicrobials using fungi and actinobacteria

Attributes:
- Readily available
- Inexpensive
- Chemically stable
- Easily administered
- Nontoxic and nonallergenic
- Selectively toxic against a wide range of pathogens
Modes of Action:
- Inhibiting Growth:
- -static: inhibits growth
- -cidal: kills organisms
- Synergistic vs Antagonistic:
- Synergistic: drugs work together for greater effect
- Antagonistic: drugs negate each other's effects

Definition: Number of different pathogens a drug acts against.
Types:
- Narrow-spectrum: effective against few organisms
- Broad-spectrum: effective against many organisms
- Risks:
- May allow for secondary or superinfections to develop
- Killing normal flora reduces microbial antagonism

Considerations:
- Select optimum dosage to minimize side effects while achieving clinical cure
- Consider half-life: the rate at which 50% of a drug is eliminated from plasma
- Dosage considerations for children under 12 years old
- Route of administration

Toxicity:
- Causes of adverse reactions are often poorly understood
- Possible damage to kidneys, liver, or nerves
- Need careful consideration when prescribing to pregnant women
Therapeutic Index:
- Ratio of the dose that can be tolerated to the drug's effective dose

Allergic reactions are rare but may be life-threatening (e.g., anaphylactic shock)
Disruption of normal microbiota can result in secondary infections
Specific risk for hospitalized patients

Assessed using:
- Diffusion Susceptibility Test
- Minimum Inhibitory Concentration (MIC) Test
- Minimum Bactericidal Concentration Test

Distinction between different types of antimicrobials:
- Semisynthetics: chemically altered antibiotics, more effective or stable
- Synthetics: entirely lab-created antimicrobials
Selective Toxicity:
- Essential for successful chemotherapy
Superinfection: development of secondary infections due to disruption of normal flora
Bactericidal vs Bacteriostatic:
- Fewer drug options for eukaryotic infections
- Limitations with antiviral drugs

Prevents bacteria from increasing peptidoglycan amounts
Most common agents disrupt NAM subunit cross-linking (e.g., beta-lactams)
- Beta-lactams (e.g., penicillins, cephalosporins): functional groups have beta-lactam rings
Semisynthetic derivatives offer advantages:
- More stable in acidic environments
- Easier absorption and resistance to deactivation
Examples:
- Vancomycin: interferes with peptide bridges in Gram-positive bacteria
- Bacitracin: blocks NAM and NAG transport
- Isoniazid & Ethambutol: disrupt mycolic acid formation

Certain drugs form channels in cytoplasmic membranes, disrupting integrity
- Polymyxins: disrupt Gram-negative bacterial membranes
- Lipopeptides: disrupt Gram-positive bacterial membranes

Antimetabolic Agents: Effective when differentiation in pathogen and host metabolic processes exists
Heavy metals can inactivate enzymes

Drugs blocking DNA replication or RNA transcription:
- Quinolones & Fluoroquinolones: act against prokaryotic DNA gyrase
Nucleotide or Nucleoside Analogs: distort nucleic acids, preventing replication/transcription/translation
- Often used against viruses
- Also effective against rapidly dividing cancer cells

Inhibition of Cell Wall Synthesis in Fungi:
- Fungal walls made of unique polysaccharides; not found in mammalian cells
- Echinocandins: inhibit glucan synthesis
Disruption of Cytoplasmic Membranes:
- Amphotericin B: binds to ergosterol in fungal membranes (with some human susceptibility)
- Azoles and Allylamines: inhibit ergosterol synthesis
Inhibition of Nucleic Acid Synthesis:
- Flucytosine: targets RNA/DNA synthesis
Disruption of Microtubule Function:
- Griseofulvin: disrupts microtubules
Inhibition of Mitochondrial Function:
- Naphthoquinone: disrupts mitochondria in parasites

Some pathogens are naturally resistant to certain drugs
Resistance can be acquired via:
- New mutations in chromosomal genes
- Acquisition of R plasmids through transformation, transduction, and conjugation

Efflux Pumps: Transport antimicrobial drugs out of the cell, preventing accumulation
Blocked Penetration: Alterations to outer membrane (lipid composition, porins) that prevent drug accumulation
Target Modification: Modify target proteins that prevent drug binding

Pathogens can acquire resistance to multiple drugs, often through R plasmids
Multi-drug resistant pathogens resist at least three antimicrobial agents
Cross Resistance: Occurs when resistance to one drug confers resistance to others