Antimicrobial Drugs and Resistance

Introduction to Antimicrobial Drugs

• Antibiotics specifically target bacteria, not viruses.
• First antibiotic, penicillin, discovered by Alexander Fleming in $1928$ from fungal inhibition of bacterial growth.
• Antibiotics can be natural, semisynthetic (chemically modified natural), or synthetic.
• Continuous modification of antibiotics is crucial due to bacterial resistance and to improve spectrum, stability, and lower toxicity.

Types of Antimicrobial Action

• Bacteriostatic: Reversibly inhibits bacterial growth; suitable for patients with strong immune systems.
• Bactericidal: Kills target bacteria; essential for immunocompromised patients.

Factors for Choosing Antimicrobials

• Type of infection, patient's immune status, spectrum of activity, dosage, route of administration, side effects, and drug interactions.
• Narrow-spectrum drugs: Effective against limited types of microbes; preferred when pathogen is known to minimize damage to beneficial bacteria.
• Broad-spectrum drugs: Effective against a wide range of microbes; used for serious systemic infections, fast-moving infections (when ID is pending), mixed infections, prophylaxis, or antibiotic failure.
• Superinfection: A secondary infection occurring during a pre-existing one, often caused by broad-spectrum antibiotics killing off normal microbiota, allowing resistant pathogens to overgrow.

Dosage and Administration

• Dosage: Must be high enough for clinical cure but low enough to minimize side effects; consider age, mass, medical history, half-life, and whether it's dose-dependent or time-dependent.
• Route of Administration: Oral (convenient), Parenteral (IV/IM for faster, higher therapeutic levels), Topical (for superficial infections to avoid systemic side effects).
• Drug Interactions:
  • Synergistic: Beneficial combined effect (1+1>2), e.g., Bactrim + Trimethoprim.
  • Antagonistic: Harmful combined effect (loss of activity, increased toxicity), e.g., antacids reducing antibiotic absorption.

Mechanisms of Antibiotic Action

Most antibiotics inhibit biosynthesis. Effectiveness is reduced when bacteria enter stationary phase and shut down synthesis.

• Inhibition of Cell Wall Synthesis: Highly selectively toxic (humans lack cell walls), often bactericidal.
  • Beta-lactam drugs (e.g., Penicillin): Inactivate transpeptidase (enzyme for peptidoglycan synthesis). Susceptible to beta-lactamase (e.g., penicillinase) enzymes produced by bacteria.
  • Glycopeptides (e.g., Vancomycin): Creates structural blockage of peptidoglycan synthesis. Effective against Gram-positives, not Gram-negatives (cannot penetrate outer membrane).
  • Bacitracin: Blocks transport of cell wall materials.
• Inhibition of Protein Synthesis: Target prokaryotic ribosomes ($70S$) to prevent accurate protein formation. Examples: Aminoglycosides (streptomycin), Tetracyclines. Can have toxic side effects as mitochondria have $70S$ ribosomes.
• Inhibition of Nucleic Acid Synthesis: Interferes with DNA replication (e.g., DNA gyrase) or RNA synthesis (e.g., RNA polymerase).
• Inhibition of Membrane Function: Disrupts lipids in bacterial membranes. For fungi, often target ergosterol (unique to fungi) synthesis or chitin cell wall synthesis.
• Inhibition of Metabolic Pathways: Synthetic substances act as competitive inhibitors of enzymes in essential metabolic pathways, e.g., sulfonamides inhibit folic acid synthesis.

Other Antimicrobials

• Antifungals: Target chitin cell wall synthesis or ergosterol in cell membranes (e.g., polyenes, azoles).
• Antiprotozoans: Produce reactive oxygen compounds, disrupt detoxification (e.g., antimalarials like quinolone).
• Antihelminthic drugs: Disrupt microtubule formation, block neuronal transmissions (e.g., Avermectin), inhibit ATP formation, interfere with ion balance or RNA synthesis.
• Antivirals: Interfere with nucleic acid biosynthesis, block viral enzymes (e.g., reverse transcriptase inhibitors for HIV), prevent viral entry or escape from host cells (e.g., Tamiflu for influenza).

Drug Resistance

• Causes: Natural bacterial protection, widespread use of antimicrobials creating selective pressure, patient non-compliance (sub-therapeutic dosing), use in agriculture, and spread in communities.
• Mechanisms of Resistance:
  • Drug modification/inactivation: Directly breaking down the antibiotic (e.g., penicillinase breaking beta-lactam ring).
  • Prevention of drug uptake: Altering membrane porosity or using efflux pumps to expel the antibiotic.
  • Target modification: Changing the antibiotic's target (e.g., ribosomes, enzymes) so it no longer binds effectively.
  • Target overproduction: Producing excess target molecules to compensate for those blocked by the antibiotic.
  • Enzymatic bypass: Using alternative metabolic pathways to achieve necessary functions.
• Superbugs: Multidrug-resistant organisms with one or more resistance mechanisms. Examples include MRSA (Methicillin-Resistant Staphylococcus aureus), VRSA (Vancomycin-Resistant Staphylococcus aureus), MDR-TB (Multidrug-Resistant Tuberculosis), and ESKAPE pathogens. Rapid identification is crucial to limit spread.