Antimicrobial Chemotherapy: Principles, Drug Classes, and Resistance

Chapter 12: Drugs, Microbes, Host – The Elements of Chemotherapy

Introduction to Antimicrobial Chemotherapy

Antimicrobial chemotherapy refers to the use of chemicals to treat infectious diseases caused by microorganisms. This chapter explores the history, principles, mechanisms, and challenges of antimicrobial drug therapy, focusing on the interactions between drugs, microbes, and the host.

Principles of Antimicrobial Therapy

Key Terminology

• Chemotherapy: Treatment of disease with chemicals. In microbiology, it refers to antimicrobial chemotherapy, not just cancer treatment.

• Chemotherapeutic drugs: Chemicals used for treatment, relief, or prevention (prophylaxis) of disease.

• Antimicrobial drugs: Compounds that destroy or inhibit microorganisms. Includes antibiotics, synthetic, and chemosynthetic drugs.

• Antibiotics: Substances produced by microorganisms that inhibit or destroy other microbes.

• Synthetic drugs: Laboratory-derived compounds, often from dyes or organic chemicals.

• Narrow spectrum: Effective against a limited range of microbes (e.g., bacitracin for Gram-positive bacteria).

• Broad spectrum: Active against a wide variety of microbes (e.g., tetracycline).

Traits of Ideal Chemotherapeutic Drugs

• Destroys the infectious agent without harming the host

• Can be administered via various routes (IV, IM, oral, topical)

• Dissolves in body fluids and reaches the infected area

• Is eventually excreted or broken down safely by the host

• No single drug possesses all ideal qualities

Origins of Antimicrobial Drugs

• Produced mainly by aerobic spore-forming bacteria and fungi

• Bacterial genera: Streptomyces, Bacillus

• Fungal genera: Penicillium, Cephalosporium

Measuring Drug Effectiveness

• Therapeutic Index (TI): Ratio of toxic dose to effective dose. $TI = \frac{\text{Toxic Dose}}{\text{Effective Dose}}$ The higher the TI, the safer the drug.

• Minimum Inhibitory Concentration (MIC): The lowest concentration of a drug that inhibits microbial growth. Determined by serial dilution and observation of growth inhibition.

• Disc Diffusion Method: Used to test bacterial sensitivity to antibiotics. The zone of inhibition around an antibiotic disc indicates effectiveness.

Drug-Microbe and Drug-Host Interactions

Drug-Microbe Interactions: Mechanisms of Action

Antimicrobial drugs target specific structures or processes in microbes. The main mechanisms include:

1. Inhibition of Cell Wall Synthesis

   • Penicillins, Cephalosporins, Vancomycin, Bacitracin, Monobactams

   • Block peptidoglycan synthesis, leading to cell lysis

2. Inhibition of Nucleic Acid Synthesis

   • Quinolones (e.g., ciprofloxacin): Inhibit DNA gyrase

   • Rifampin: Inhibits RNA polymerase

3. Inhibition of Protein Synthesis

   • 30S subunit: Aminoglycosides (streptomycin, gentamicin), Tetracyclines

   • 50S subunit: Chloramphenicol, Erythromycin, Clindamycin

4. Disruption of Cell Membrane Function

   • Polymyxins: Distort membrane, cause leakage

   • Polyene antifungals (amphotericin B, nystatin): Form complexes with sterols

5. Inhibition of Metabolic Pathways

   • Sulfonamides: Competitive inhibitors of folic acid synthesis

   • Trimethoprim: Inhibits synthesis of tetrahydrofolic acid

   • Synergistic effect: Combination therapy enhances efficacy

Survey of Major Antimicrobial Drug Groups

Antibacterial Drugs

Drug Class	Mechanism/Target	Spectrum	Examples	Notes
Beta-Lactams	Cell wall synthesis	Narrow/Broad	Penicillins, Cephalosporins	Penicillins mostly narrow; cephalosporins broad
Aminoglycosides	Protein synthesis (30S)	Broad	Streptomycin, Gentamicin, Neomycin	Effective against Gram-negative rods
Tetracyclines	Protein synthesis (30S)	Broad	Tetracycline, Doxycycline	Side effects: GI upset, deposition in tissues
Chloramphenicol	Protein synthesis (50S)	Broad	Chloramphenicol	Risk of aplastic anemia
Macrolides	Protein synthesis (50S)	Broad	Erythromycin, Clindamycin	Low toxicity (erythromycin); clindamycin is toxic
Vancomycin	Cell wall synthesis	Narrow	Vancomycin	Used for life-threatening infections
Rifampin	RNA synthesis	Narrow	Rifampin	Used for Gram-positive rods/cocci
Polymyxins	Cell membrane	Narrow	Polymyxin B	Toxic; used topically
Sulfonamides/Trimethoprim	Folic acid synthesis	Broad	Sulfanilamide, Trimethoprim	Synergistic effect
Fluoroquinolones	DNA synthesis	Broad	Ciprofloxacin	High potency

Other Antimicrobials

• Antifungal Drugs: Many end in "-azole" (e.g., miconazole, itraconazole, fluconazole). Others include amphotericin B (systemic infections), nystatin (yeast infections), flucytosine.

• Antiparasitic Drugs: Quinine (antimalarial), amebocides (kill amoebas), antihelminths (kill worms).

• Antiviral Drugs: Target stages of viral replication (e.g., ribavirin, AZT, acyclovir, protease inhibitors, interferon, amantadine).

Antimicrobial Resistance

Mechanisms of Resistance

• Drug Inactivation: Enzymes (e.g., beta-lactamases) destroy the drug (e.g., penicillin resistance).

• Decreased Permeability: Altered receptors prevent drug entry.

• Efflux Pumps: Drugs are pumped out of the cell (e.g., tetracycline resistance).

• Altered Drug Targets: Changes in ribosomal subunits prevent drug binding (e.g., erythromycin resistance).

• Alternative Metabolic Pathways: Bypass the blocked step (e.g., sulfa drug resistance).

Genetic Basis of Resistance

• Vertical transmission: Resistance genes passed from parent to offspring.

• Horizontal transmission: Genes transferred via plasmids (R-factors) through conjugation, transformation, or transduction.

Human Role in Resistance Development

• Overprescription and misuse of antibiotics (especially for viral infections)

• Use of broad-spectrum antibiotics

• Antibiotic use in livestock feed

• Poor infection control in hospitals

• Global travel spreading resistant strains

Prevention of Resistance

• Prescribe antibiotics only when necessary and after identifying the causative agent

• Educate patients to complete prescriptions and not share drugs

• Implement global and national policies to restrict antibiotic use

New Approaches to Antimicrobial Therapy

• Riboswitches: Control translation of mRNA

• Prevention of iron scavenging by pathogens

• Probiotics: Replenish normal flora

• Prebiotics: Promote growth of beneficial microbes

• Fecal transplants: Restore microbiota (e.g., for Clostridium difficile infections)

Drug-Host Interactions

Side Effects of Antibiotics

• Toxicity to Organs: Some drugs (e.g., chloramphenicol) can damage organs.

• Allergic Reactions: Hypersensitivity (e.g., penicillin allergy).

• Suppression/Alteration of Microflora: Loss of normal flora can lead to overgrowth of resistant or opportunistic pathogens (e.g., Clostridium difficile, Candida albicans).

Summary Table: Major Antimicrobial Drug Classes and Their Targets

Drug Class	Target	Example(s)	Notes
Beta-Lactams	Cell wall	Penicillins, Cephalosporins	Resistance via beta-lactamases
Aminoglycosides	Protein synthesis (30S)	Streptomycin, Gentamicin	Nephrotoxic, ototoxic
Tetracyclines	Protein synthesis (30S)	Tetracycline, Doxycycline	Broad spectrum, GI side effects
Macrolides	Protein synthesis (50S)	Erythromycin	Low toxicity
Chloramphenicol	Protein synthesis (50S)	Chloramphenicol	Risk of aplastic anemia
Polymyxins	Cell membrane	Polymyxin B	Topical use only
Sulfonamides	Folic acid synthesis	Sulfanilamide	Synergistic with trimethoprim
Fluoroquinolones	DNA synthesis	Ciprofloxacin	Broad spectrum
Antifungals	Membrane sterols, nucleic acid synthesis	Amphotericin B, Azoles	Systemic and superficial infections
Antivirals	Various viral processes	AZT, Acyclovir, Protease inhibitors	Target replication, assembly, release

Example: Triple Antibiotic Ointment (Neosporin™)

• Bacitracin: Cell wall inhibitor (narrow spectrum)

• Polymyxin: Cell membrane inhibitor (narrow spectrum, toxic to kidneys, topical use)

• Neomycin: Aminoglycoside (protein synthesis inhibitor, 30S subunit)

Additional info:

• Combination therapy (e.g., sulfonamides + trimethoprim) is used to enhance efficacy and reduce resistance development.

• Probiotics and fecal transplants are emerging as adjunct therapies to restore healthy microbiota after antibiotic treatment.