Antimicrobial Drugs

Mechanisms of Antimicrobial Action

Antimicrobial drugs are designed to interfere with the metabolism or structure of microorganisms, preventing their survival or reproduction. These agents can be microbicidal (killing microbes) or microbiostatic (inhibiting growth reversibly).

• Microbicidal: Kills microbes, including normal flora, which may lead to superinfection.

• Microbiostatic: Inhibits microbial growth without killing, allowing recovery of normal flora after treatment.

Five Basic Mechanisms of Action

• Inhibition of Cell Wall Synthesis: Weakens peptidoglycan layer, making bacteria vulnerable to lysis. Examples: Penicillin, Cephalosporins.

• Inhibition of Protein Synthesis: Disrupts translation at the ribosome. Bacterial ribosomes differ from eukaryotic ribosomes, so human cells are usually unaffected. Examples: Tetracyclines, Aminoglycosides.

• Inhibition of Nucleic Acid Synthesis: Disrupts DNA and RNA synthesis, including nucleotide component synthesis, DNA replication, and RNA transcription. Often involves competitive inhibition.

• Disruption of Plasma Membrane: Affects transport and weakens cell integrity. Can affect both prokaryotic and eukaryotic cells.

• Inhibition of Metabolic Pathways: Disrupts enzyme activity and production, affecting essential metabolic compounds.

Characteristics of Antimicrobial Agents

Effective antimicrobial agents possess several important characteristics that determine their clinical utility.

• Spectrum of Action: Range of microorganisms affected. Broad spectrum targets many types; narrow spectrum targets few, reducing impact on normal flora.

• Selective Toxicity: Ideally, drugs kill only pathogens without harming the host. Determined by toxic dosage vs. therapeutic dosage.

• Microbicidal vs. Microbiostatic: Bactericidal drugs kill bacteria; bacteriostatic drugs inhibit growth.

• Delivery to Infection Site: Efficacy depends on overcoming barriers (e.g., blood-brain barrier), solubility, and achieving sufficient concentration.

• Time of Activity: Duration of drug activity affects effectiveness and resistance development.

• Degree of Resistance: Resistance can develop via genetic mutations or acquisition of resistance genes.

• Complements Host Defense: Drugs may be needed when host defenses are compromised.

• Stability and Shelf Life: Longer shelf life improves storage and availability.

• Allergenic Potential: Risk of allergic reactions must be considered.

• Affordability and Availability: Practical considerations for widespread use.

Spectrum of Action

• Broad Spectrum: Effective against many microorganisms.

• Narrow Spectrum: Targets a limited group, minimizing disruption to normal flora.

• Medium Spectrum: Effective against some gram-positive and gram-negative bacteria.

Therapeutic Index

The therapeutic index is the ratio between the toxic dose and the therapeutic dose of a drug. A higher therapeutic index indicates greater safety.

• Formula:

Side Effects

• Potential organ damage: liver, gastrointestinal tract, kidneys, cardiovascular system, red bone marrow, nervous system, respiratory system, integument, bones, and teeth.

Determination of Efficacy

Several laboratory methods are used to determine the effectiveness of antimicrobial agents.

• Kirby-Bauer (Disk Diffusion) Method: Measures zone of inhibition around antibiotic disks to assess effectiveness.

• Minimal Inhibitory Concentration (MIC) Method: Identifies the lowest concentration of antibiotic that inhibits growth. Turbidity indicates growth; lack of turbidity indicates inhibition.

• Serum Killing Power: Uses patient serum to determine effective antibiotic concentration.

Table: Methods for Determining Antimicrobial Efficacy

Resistance to Antimicrobial Drugs

Development and Mechanisms of Resistance

Microorganisms can develop resistance to antimicrobial drugs through genetic and nongenetic mechanisms. Resistance is a major global health concern, especially in healthcare settings.

• Genetic Mechanisms: Mutations, acquisition of resistance genes via conjugation, transformation, and transduction.

• Nongenetic Mechanisms: L-forms (cell wall-deficient variants).

Mechanisms of Resistance

• Change in membrane permeability

• Increased drug elimination

• Change in target (receptor)

• Change in metabolic pathway

• Change in previously inhibited enzyme

• Development of defensive enzymes

Multiple Resistances

• Improper use of antibiotics leads to "superbugs" with multiple resistances.

• Cross-resistance: resistance to multiple drugs with similar mechanisms.

Controlling Drug Resistance

• Hand washing

• Eliminate unwarranted antibiotic use

• Target narrow range of microbes

• Use drug combinations (synergism)

• Isolate facilities with ongoing infections

• Follow current data and guidelines

• Take antibiotics as prescribed; discard leftovers

• Do not use others' prescriptions

• Judicious use of antimicrobial soaps and lotions

• Prevent disruption of normal flora

Classes of Antimicrobial Agents

Antibacterial Agents

• Natural Antibiotics: Produced by microorganisms.

• Semisynthetic Antibiotics: Chemically modified natural antibiotics.

• Synthetic Drugs: Produced in laboratory.

Table: Types of Antibacterial Agents

Examples of Antibacterial Agents

• Sulfonamides: First synthetic antimicrobial, disrupts bacterial metabolism.

• Trimethoprim: Used with sulfonamides.

• Quinolones: Broad spectrum synthetic.

• Penicillins: Produced by Penicillium chrysogenum; semisynthetic types include ampicillin and methicillin.

• Cephalosporins: Structurally similar to penicillins; used for penicillin-allergic patients.

• Tetracyclines: Broad spectrum, inhibit protein synthesis.

• Aminoglycosides: Bactericidal, toxic, resistance to streptomycin.

• Macrolides: Broad spectrum, bacteriostatic, low toxicity (e.g., erythromycin).

• Chloramphenicol: Broad spectrum, high toxicity, restricted use.

• Lefamulin: Semi-synthetic, inhibits bacterial protein, used for pneumonia.

• Bacillus antibiotics: Narrow spectrum, topical (e.g., bacitracin, polymyxins).

Antiviral Agents

• Limited effectiveness; often damage host cells.

• Target viral life cycle: prevent penetration, block transcription/translation, prevent maturation.

• Acyclovir: Guanine analogue, less toxic.

• Amantadine: Prevents influenza A.

• Azidothymidine (AZT): Used for AIDS, often in combination therapy.

• Interferons: Induce antiviral agents in neighboring cells.

Antifungal Agents

• Synthetic azoles: Broad spectrum, treat superficial and systemic infections (e.g., ketoconazole).

• Flucytosine: Broad spectrum, systemic and cutaneous mycoses.

• Macrolide polyene antibiotics: Systemic mycoses.

• Griseofulvin: Narrow spectrum, dermatophyte infections.

• Echinocandins: Systemic infections, prophylaxis against Pneumocystis carinii.

Antiprotozoal Agents

• Chloroquine and primaquine: Synthetic, used for Plasmodium (malaria).

• Metronidazole: Treats Trichomonas vaginalis and Giardia infections.

• Pyrimethamine: Used with sulfanilamide for malaria and toxoplasmosis.

• Quinine: Nonsynthetic, extracted from cinchona bark, treats malaria.

Antihelminthic Agents

• Helminths are eukaryotic; treatment is difficult.

• Agents suppress metabolism or movement.

• Examples: Niclosamide, Mebendazole, Piperazine, Ivermectin.

Example: Penicillin inhibits cell wall synthesis, making bacteria susceptible to lysis. Acyclovir is used to treat herpes virus infections by mimicking guanine and disrupting viral DNA synthesis.

Additional info: The notes have been expanded to include definitions, examples, and context for each class of antimicrobial agent and mechanism of resistance, as well as tables summarizing key comparisons.