Principles of Antimicrobial Therapy and Drug Mechanisms

• Aminoglycosides (e.g., streptomycin) bind to the 30S subunit, causing mRNA misreading.
• Tetracyclines block the attachment of tRNA to the A site.
• Macrolides (e.g., erythromycin) inhibit the translocation of the ribosomal subunit.

3. Inhibition of Nucleic Acid Structure and Function

These drugs interfere with the microbe's ability to replicate its DNA or transcribe its RNA.

• Fluoroquinolones (e.g., ciprofloxacin) inhibit DNA unwinding enzymes like helicase.
• Ansamycins (e.g., rifampin) interfere with RNA synthesis.

4. Interference with Cell Membrane Structure or Function

Some drugs act like detergents, disrupting the integrity of the microbial cell membrane and causing the leakage of vital cellular components. Polymyxins are a notable example, particularly effective against gram-negative bacteria.

5. Inhibition of Folic Acid Synthesis

Many bacteria must synthesize their own folic acid to produce DNA, RNA, and amino acids. Sulfonamides (sulfa drugs) interfere with this metabolic pathway by blocking the enzymes required for folate synthesis.

Measuring Safety: Therapeutic Index and Window

When selecting a drug, clinicians must balance efficacy against toxicity. This is managed through two key concepts: the Therapeutic Index (TI) and the Therapeutic Window.

The Therapeutic Index (TI) is defined as the ratio of the dose of the drug that is toxic to humans to the effective dose (the dose that inhibits the microbe):

$\text{Therapeutic Index (TI)} = \frac{\text{Toxic Dose}}{\text{Effective Dose}}$

• High TI: A large ratio (e.g., 10 or higher) indicates a wide margin of safety, meaning the dose required to kill the microbe is much lower than the dose that would harm the patient.
• Low TI: A small ratio (e.g., 1.1) indicates a high risk of toxic reactions, as the effective dose is very close to the toxic dose.

The therapeutic window refers to the specific range of drug concentration in the blood that produces the desired effect without causing toxicity.

Exam Tip: If you are comparing two drugs with the same Minimum Inhibitory Concentration (MIC), always choose the one with the highest Therapeutic Index, as it provides the greatest safety margin.

Clinical Challenges in Drug Selection

Even with accurate antimicrobial sensitivity tests—such as the Kirby–Bauer disc diffusion test (which measures zones of inhibition) or tube dilution tests (which determine the Minimum Inhibitory Concentration, or MIC)—treatment failure can occur.

Clinicians must account for several complicating factors:

1. Diffusion Barriers: A drug may be highly effective in a lab setting but unable to diffuse into specific body compartments like the brain, joints, or skin.
2. Undetected Resistance: The initial diagnostic sample may not have captured all the microbes present, potentially missing resistant strains.
3. Mixed Infections: An infection may be caused by multiple different pathogens; a drug that kills one might be ineffective against another in the same host.
4. Drug Interactions: Clinicians must consider whether drugs will have synergistic effects (working together to enhance killing) or antagonistic effects (interfering with each other).
5. Microbiome Impact: Antimicrobials can disrupt the host's normal microbial biota, potentially leading to superinfections like Clostridioides difficile colitis or vaginal yeast infections.