Chapter 11

Antimicrobial Drugs

General Goal of Antimicrobial Drug Actions

Antimicrobial drugs are designed to interfere with the metabolism or structure of microorganisms, ultimately preventing their survival or reproduction. These agents can either kill the microorganism (microbiocidal) or reversibly inhibit its growth (microbiostatic).

• Microbiocidal: Kills the microorganism directly.

• Microbiostatic: Inhibits growth, allowing the immune system to eliminate the pathogen.

• Goal: Disrupt essential processes or structures unique to the pathogen.

Mechanisms of Action of Antimicrobial Drugs

Five Basic Categories of Mechanisms

Antimicrobial drugs act through five primary mechanisms, each targeting a specific aspect of microbial physiology:

• 1. Inhibition of Cell Wall Synthesis: Prevents bacteria from forming a protective peptidoglycan wall, leading to cell lysis. Example: Penicillins and cephalosporins.

• 2. Inhibition of Protein Synthesis: Interferes with translation at the ribosome. Bacterial ribosomes differ from human ribosomes, allowing selective targeting. Example: Tetracyclines, macrolides.

• 3. Inhibition of Nucleic Acid Synthesis: Disrupts DNA or RNA replication and transcription. Example: Fluoroquinolones, rifamycins.

• 4. Disruption of Cell Membrane Function: Damages the plasma membrane, causing loss of integrity and cell death. Example: Polymyxins, antifungals.

• 5. Inhibition of Metabolic Pathways (Antimetabolites): Blocks crucial enzymatic reactions or synthesis of essential compounds. Example: Sulfa drugs inhibit folic acid synthesis.

Spectrum of Activity of Antimicrobial Drugs

Classification by Spectrum

Antimicrobial drugs vary in the range of microorganisms they affect, known as their spectrum of activity:

• Broad Spectrum: Effective against a wide variety of microorganisms, including both Gram-positive and Gram-negative bacteria. May disrupt normal flora and lead to superinfections.

• Narrow Spectrum: Targets a limited group of microorganisms, minimizing disruption to normal flora.

• Medium Spectrum: Effective against some, but not all, Gram-positive and Gram-negative bacteria.

• Superinfection: Occurs when normal flora are destroyed, allowing opportunistic pathogens to proliferate (e.g., Clostridioides difficile colitis).

Factors in Selecting an Antimicrobial Drug

Key Considerations

Several factors must be evaluated when choosing an antimicrobial agent:

• Spectrum of Activity: Match the drug to the pathogen.

• Selective Toxicity: The drug should harm the pathogen without damaging the host.

• Delivery to Site: The agent must reach the infection site in effective concentrations.

• Time of Activity: Prolonged activity is desirable for effective treatment.

• Resistance Potential: Prefer drugs less likely to induce resistance.

• Nonallergenic: Avoid drugs that may cause allergic reactions in the patient.

• Stability: Shelf-stable drugs are preferred for practical use.

• Compatibility with Natural Defenses: Should not impair the host's immune response.

• Affordability: Cost-effective options are ideal.

Testing Antibiotic Efficacy

Laboratory Methods

Microorganisms vary in their susceptibility to antibiotics. Common laboratory methods to determine efficacy include:

• Kirby-Bauer Method (Disk Diffusion): Measures zones of inhibition around antibiotic disks on an agar plate.

• Dilution Method (Minimal Inhibitory Concentration, MIC): Identifies the lowest concentration of drug that inhibits growth.

• Serum Killing Power: Tests the effectiveness of a drug in a patient's serum against the pathogen.

Therapeutic Index and Side Effects

Therapeutic Index

The therapeutic index is the ratio of the toxic dose to the therapeutic dose of a drug. A higher index indicates a safer drug. All drugs carry potential risks, and side effects must be weighed against benefits.

• Hepatotoxic: Liver damage

• Nephrotoxic: Kidney damage

• Hemotoxic: Blood toxicity

• Neurotoxic: Nervous system toxicity

• Common Side Effects: Diarrhea, allergic reactions, superinfections (e.g., C. difficile colitis)

• Drug Interactions: Combining drugs can increase toxicity

Development and Mechanisms of Drug Resistance

How Resistance Develops

Microorganisms can develop resistance to antimicrobial drugs through genetic and non-genetic mechanisms. Resistance is accelerated by misuse, underuse, and poor compliance.

• Non-genetic: Evasion (hiding in tissues), alteration of cell wall (L-forms)

• Genetic: Mutation and selection for resistant strains

• Selective Pressure: Use of antibiotics selects for resistant organisms

Mechanisms of Resistance

• Change in Metabolic Pathway: Bypass inhibited steps

• Change in Membrane Permeability: Prevent drug entry

• Increased Drug Elimination: Efflux pumps remove drug

• Change in Enzyme: Alter target enzyme to avoid inhibition

• Change in Target Site: Modify binding site to prevent drug action

• Defensive Enzymes: Produce enzymes that destroy or inactivate the drug (e.g., β-lactamases)

Multiple resistance is a growing concern, especially in healthcare settings.

Controlling Drug Resistance

Prevention Strategies

• Hand hygiene between patients

• Prescribe antibiotics only when necessary

• Use narrow-spectrum drugs when possible

• Combine antibiotics to overcome resistance

• Isolate patients with multi-drug resistant infections

• Follow local resistance data

• Ensure patient compliance with prescriptions

• Do not hoard or share antibiotics

• Limit use of antimicrobial soaps to high-risk situations

Types and Actions of Antimicrobial Agents

Antibacterial Agents

• Synthetic: Manufactured entirely in the lab (e.g., sulfa drugs, fluoroquinolones)

• Semi-synthetic: Natural products chemically modified (e.g., ampicillin, azithromycin)

• Bacillus Antibiotics: Naturally produced by Bacillus species (e.g., bacitracin, polymyxins)

Antiviral Agents

• Target unique aspects of viral life cycle (e.g., entry, transcription, maturation)

• Examples: Drugs that block viral penetration, inhibit viral enzymes, or prevent maturation

Antifungal Agents

• Griseofulvin: Narrow spectrum, treats athlete's foot

• Echinocandins: Versatile, used for systemic infections

• Azoles: Broad spectrum, treat superficial infections

• Flucytosine: Broad spectrum, some skin infections

• Macrolide Polyene Antibiotics: IV for systemic infections (e.g., Candida, Aspergillus)

Antiprotozoan Agents

• Chloroquine: Synthetic, treats malaria

• Pyrimethamine: Used with sulfa drugs for malaria and toxoplasmosis

• Metronidazole: Treats Trichomonas and Giardia; side effect: "black hairy tongue"

• Quinine: Nonsynthetic, used in severe malaria cases

Antihelminthic Agents

• Niclosamide: Inhibits ATP formation, causes lactic acid release in worms

• Mebendazole: Blocks glucose uptake, not for pregnant women

• Piperazine: Neurotoxin, paralyzes roundworms

• Ivermectin: Blocks nerve transmission, treats heartworm in dogs

Summary Table: Mechanisms of Antimicrobial Action

Mechanism	Target	Example Drugs
Cell Wall Synthesis Inhibition	Peptidoglycan	Penicillins, Cephalosporins
Protein Synthesis Inhibition	Ribosomes	Tetracyclines, Macrolides
Nucleic Acid Synthesis Inhibition	DNA/RNA Polymerases	Fluoroquinolones, Rifamycins
Cell Membrane Disruption	Plasma Membrane	Polymyxins, Daptomycin
Metabolic Pathway Inhibition	Enzymes (e.g., folic acid synthesis)	Sulfa drugs, Trimethoprim