Antimicrobial Chemotherapy

History of Antimicrobial Discovery

• Penicillin: First discovered by Ernest Duchesne ($1896$), then accidentally rediscovered by Alexander Fleming ($1928$) on a contaminated plate. Its effectiveness was demonstrated by Florey, Chain, and Heatley ($1939$). Fleming, Florey, and Chain received the Nobel Prize in $1945$.

• Streptomycin: Discovered by Selman Waksman ($1944$) for tuberculosis treatment; he received the Nobel Prize in $1952$.

• Later Discoveries: By $1953$, chloramphenicol, neomycin, oxytetracycline, and tetracycline were isolated.

General Characteristics of Antimicrobial Drugs

• Selective Toxicity: Ability to damage pathogens while minimizing host harm.

• Therapeutic Dose: Drug level required for clinical treatment.

• Toxic Dose: Drug level where it becomes too toxic for the patient (produces side effects).

• Therapeutic Index (TI): The ratio defined as $TI = rac{TD_{50}}{ED_{50}}$.

• Terms:     - $TD_{50}$: Dose causing toxic response in $50\,\%$ of the population.     - $ED_{50}$: Dose therapeutically effective in $50\,\%$ of the population.     - Narrow-spectrum: Attacks few pathogens.     - Broad-spectrum: Attacks many types of bacteria.     - Cidal agent: Kills the target pathogen.     - Static agent: Reversibly inhibits growth.

Measuring Effectiveness of Antimicrobial Drugs

• Minimal Inhibitory Concentration (MIC): Lowest drug concentration preventing pathogen growth.

• Minimal Lethal Concentration (MLC): Lowest drug concentration that kills the pathogen.

• Dilution Susceptibility Tests: Involve inoculating media with different drug concentrations to determine MIC and MLC.

• Kirby-Bauer Method: Standardized disk diffusion test where zone diameters are used to determine resistance or sensitivity.

Antibacterial Drugs: Cell Wall and Protein Synthesis Inhibitors

• Inhibitors of Cell Wall Synthesis:     - Penicillins: Derivatives of $6$-aminopenicillanic acid; characterized by a $\beta$-lactam ring. Often bactericidal; Staphylococcus aureus and many Streptococcus strains are resistant.     - Cephalosporins: Used for respiratory infections and UTIs; effective against Gram-positives; Escherichia coli and Klebsiella are resistant.     - Vancomycin: Glycopeptide antibiotic used for resistant staphylococcal and enterococcal infections; formerly the "drug of last resort."

• Protein Synthesis Inhibitors:     - Aminoglycosides: Bactericidal; effective against Gram-negative bacteria; Pseudomonas aeruginosa is resistant.     - Tetracyclines: Broad-spectrum; targets the ribosome; common for acne; Shigella species are resistant.     - Macrolides: Contain a lactone ring; inhibits protein elongation; Streptococcus pneumoniae is resistant.     - Chloramphenicol: Chemically synthesized; broad-spectrum but toxic; used for life-threatening situations; Pseudomonas species are resistant.

Metabolic Antagonists and Nucleic Acid Inhibition

• Sulfonamides (Sulfa Drugs): Competitive inhibition of folic acid synthesis; used for UTIs; Neisseria meningitidis and gonorrhoea are resistant.

• Nucleic Acid Synthesis Inhibition:     - Fluoroquinolones: Inhibit DNA gyrase and topoisomerase II; bactericidal; broad-spectrum.     - Rifamycins: Inhibit RNA polymerase.

Antiviral and Antifungal Drugs

• Antivirals: Target specific enzymes; limited success due to difficulty in targeting viral replication without harming the host.     - Influenza: Tamiflu (neuraminidase inhibitor).     - Herpes/Shingles: Acyclovir and Ganciclovir (inhibit viral polymerase).     - HIV: Categories include NRTIs (nucleoside reverse transcriptase inhibitors), Protease inhibitors (PIs), Fusion inhibitors, and Integrase inhibitors.

• Antifungals: Low therapeutic index due to similarities between fungal and human cells.     - Superficial: Candida treatment; disrupt sterol synthesis or membrane permeability.     - Systemic: Amphotericin B (binds sterols), $5$-flucytosine (disrupts RNA), and Fluconazole.

Drug Resistance

• Types:     - Intrinsic: Naturally lacking a target ($\text{e.g.}$, Mycoplasma lacks cell walls).     - Acquired: Change in genome via mutation or horizontal transfer.     - Persisters (Drug-tolerant): Bacteria in biofilms that "ignore" drugs due to lack of penetration or slow growth.

• Mechanisms: Target modification, drug inactivation, minimization of concentration (efflux), or bypass of biochemical reactions.

• Detection: PCR for resistance genes, chromophores for $\beta$-lactamase detection, and gene expression systems.

• Future Solutions: Use of bacteriophages and development of new drugs.