Chapter 15: Antimicrobial Drugs – Principles, Mechanisms, and Resistance

Introduction to Antimicrobial Drugs

Historical Context and Discovery

Antimicrobial drugs are therapeutic compounds that kill or inhibit the growth of microbes. Their development revolutionized modern medicine, drastically reducing mortality from infectious diseases.

• Alexander Fleming discovered penicillin in 1928 from the mold Penicillium while studying Staphylococcus aureus. He observed that bacteria did not grow near the mold.

• Penicillin was mass-produced in the 1940s, especially during WWII.

• Another key antibiotic, streptomycin, was isolated from Streptomyces griseus and is still used to treat tuberculosis.

Definitions and Classifications

• Antibiotic: A naturally occurring antimicrobial compound produced by microorganisms.

• Antimicrobial drug: Any agent (natural, semisynthetic, or synthetic) that kills or inhibits microbes.

• Spectrum of activity: The range of microbes an antimicrobial targets.

• Broad-spectrum drugs: Effective against a wide variety of Gram-positive and Gram-negative bacteria. Drawback: Increased risk of disrupting normal microbiota and causing Clostridioides difficile infection.

• Narrow-spectrum drugs: Target a limited range of bacteria. Preferred to minimize disruption of normal flora but require knowledge of the pathogen.

• Empiric therapy: Treatment based on clinical presentation before definitive pathogen identification, often using broad-spectrum drugs.

Bacteriostatic vs. Bactericidal Drugs

• Bacteriostatic drugs: Inhibit bacterial growth (e.g., by targeting protein synthesis or metabolic pathways). Effective when the patient's immune system can clear the infection.

• Bactericidal drugs: Kill bacteria directly (e.g., by targeting cell walls, membranes, or nucleic acids). May also kill normal microbiota and can cause toxin release (e.g., endotoxin from Gram-negative bacteria).

• Note: The same drug may be bacteriostatic for one pathogen and bactericidal for another, depending on factors such as dose, pathogen type, and route of administration.

Natural, Semisynthetic, and Synthetic Antimicrobials

• Natural antibiotics: Produced by microorganisms in nature.

• Synthetic antimicrobials: Fully manufactured by chemical processes.

• Semisynthetic antimicrobials: Chemically modified derivatives of natural antibiotics.

• Drug modifications (e.g., changing R groups) can improve spectrum, stability, and resistance circumvention.

Generations of Antimicrobial Drugs

• First-generation: Initial chemical modification.

• Second-generation: Further modification for improved properties.

• Third-generation: Additional modifications for expanded capabilities (e.g., extended spectrum, increased stability).

Drug Safety and Administration

Selective Toxicity and Therapeutic Index

• Selective toxicity: The drug should harm the pathogen without harming host cells.

• Therapeutic index: Ratio of maximum safe dose to minimum effective dose. $\text{Therapeutic Index} = \frac{\text{Maximum Safe Dose}}{\text{Minimum Effective Dose}}$ Higher values indicate safer drugs.

Toxicity Considerations

• Nephrotoxic drugs: Harm the kidneys (e.g., some antimicrobials).

• Hepatotoxic drugs: Harm the liver (e.g., antimicrobials causing drug-induced liver injury, DILI).

• Nearly all drugs have contraindications or warnings.

Routes of Administration

• Oral: Preferred for ease; drug must be stable in stomach acid and absorbed in intestines.

• Parenteral: Injection or infusion (intravenous, intramuscular, subcutaneous). Used when oral route is not feasible.

Drug Stability and Elimination

• Drug half-life: Time for half the drug dose to be eliminated or deactivated. Determines dosing frequency.

• Examples:

  • Penicillin V: half-life ~30 min (dosed every 4 hours for 7–10 days)

  • Azithromycin: half-life up to 68 hours (dosed every 24 hours for 3–5 days)

Survey of Antibacterial Drugs

Overview

Antibacterial drugs are more common due to the unique features of prokaryotic cells, making selective toxicity easier to achieve compared to viruses and eukaryotic pathogens.

• Viruses use host cell machinery, and eukaryotic pathogens share many features with human cells, complicating drug development.

Cellular Targets of Antibacterial Drugs

The ideal antibacterial drug targets structures/processes unique to bacteria, such as the cell wall, 70S ribosome, unique enzymes, or metabolic pathways.

Target	Action	Drug Family	Examples	Activity Spectrum
Cell wall synthesis	Bactericidal	Penicillins	Penicillin G, Amoxicillin	Narrow (natural); Broad (some semisynthetic)
Cell wall synthesis	Bactericidal	Cephalosporins	Ceftriaxone, Cephalexin	Broad
Cell wall synthesis	Bactericidal	Carbapenems	Imipenem, Meropenem	Broad
Cell wall synthesis	Bactericidal	Monobactams	Aztreonam	Narrow
Cell wall synthesis	Bactericidal	Glycopeptides	Vancomycin	Narrow
Protein synthesis (50S ribosome)	Bacteriostatic	Macrolides	Erythromycin, Azithromycin	Broad
Protein synthesis (50S ribosome)	Bacteriostatic	Lincosamides	Clindamycin	Broad
Protein synthesis (50S ribosome)	Bacteriostatic	Phenicols	Chloramphenicol	Broad
Protein synthesis (30S ribosome)	Bacteriostatic	Tetracyclines	Doxycycline, Tetracycline	Broad
Protein synthesis (30S ribosome)	Bactericidal	Aminoglycosides	Gentamicin, Streptomycin	Narrow
Nucleic acid synthesis	Bactericidal	Rifamycins	Rifampin	Broad
Nucleic acid synthesis	Bactericidal	Quinolones	Ciprofloxacin	Broad
Folic acid synthesis	Bacteriostatic	Sulfa drugs	Sulfamethoxazole	Broad
Cell membrane	Bactericidal	Polypeptide drugs	Polymyxin B, Colistin	Narrow

Additional info: Table reconstructed and summarized from slides and standard microbiology references.

Drugs for Viral and Eukaryotic Infections

Challenges in Drug Development

• Viruses replicate inside host cells, making selective toxicity difficult.

• Eukaryotic pathogens (fungi, protozoa, helminths) share many cellular features with humans, increasing the risk of toxicity.

Antiviral Drugs

• Target specific stages of viral replication:

  • Attachment

  • Penetration

  • Uncoating

  • Viral replication and assembly

  • Viral release

• Some drugs (e.g., interferons) stimulate immune responses against viruses.

• Most effective against actively replicating viruses (e.g., HIV, herpesviruses, hepatitis, influenza).

Antifungal Drugs

• Target fungal cell walls (unique from bacteria and humans), plasma membranes (ergosterol), or nucleic acid synthesis.

• Drawback: Some antifungals can interfere with human cholesterol metabolism.

Antiprotozoal and Antihelminthic Drugs

• Target intracellular components or metabolic pathways unique to parasites.

• Development is challenging due to complex life cycles and similarity to human cells.

Drug Resistance and Antimicrobial Stewardship

Antimicrobial Resistance

• Occurs when microbes are not affected by drugs intended to inhibit or eliminate them.

• Resistant bacteria are called superbugs.

• Superinfections occur when resistant microbes become the dominant pathogens during treatment.

Types of Resistance

• Intrinsic resistance: Natural resistance due to inherent structural or functional characteristics (e.g., Mycoplasma pneumoniae lacks a cell wall; Clostridioides difficile forms endospores).

• Acquired resistance: Results from mutations or horizontal gene transfer (conjugation, transformation, transduction).

Mechanisms of Drug Evasion

• Altering the drug target (e.g., mutation in enzyme structure).

• Inactivating the drug (e.g., enzymatic breakdown or modification).

• Reducing drug concentration inside the cell (e.g., efflux pumps, reduced permeability).

Human Behaviors and Resistance Emergence

• Antibiotic resistance is driven by natural selection and misuse (e.g., not completing prescriptions, using antibiotics for viral infections).

• Agricultural use of antibiotics in animal feed promotes resistance.

• Healthcare settings are high-risk environments for resistance development and spread.

Resistant Microbes to Watch (CDC, 2017)

Urgent Threats	Serious Concern
Clostridioides difficile Carbapenem-resistant Enterobacterales (CRE) Neisseria gonorrhoeae Candida auris	Campylobacter Candida (yeast) Pseudomonas Mycobacterium Staphylococcus Streptococcus

Combating Resistance: Stewardship and New Drug Development

• Proper antimicrobial stewardship is essential (e.g., hand hygiene, limiting unnecessary prescriptions, patient education).

• Developing new drugs is costly and time-consuming (10–15 years, near a billion dollars per drug).

• Few pharmaceutical companies invest in new antimicrobials due to lower profitability compared to chronic medications.

• Innovative approaches include multidrug combinations, phage therapy, and extending patent rights for new drugs.