Micro Unit 6 pt 2

Introduction to Antimicrobial Medications

• Presenter: Dr. Rachael Romain

• Subject: BIO 2215 Antimicrobial Medications

• Copyright Notice: The McGraw-Hill Companies, Inc. - Permission required for reproduction or display.

Fundamental Terminology

• Antibiotic vs Antimicrobial

  • Antibiotic: A type of antimicrobial specifically derived from biological organisms that can kill or inhibit bacteria.

  • Antimicrobial: A broader term that encompasses any substance that kills or inhibits the growth of microorganisms, including bacteria, fungi, parasites, and viruses.

• Classification of Bacteria

  • Gram-positive (Gram +): Retain crystal violet stain and appear purple under a microscope.

  • Gram-negative (Gram -): Do not retain the crystal violet stain and appear pink due to the presence of a thinner peptidoglycan cell wall and an outer membrane.

  • Gram-positive AND Gram-negative: Refers to activities or effects applicable to both types.

Historical Development of Antimicrobial Drugs

Key Discoveries

• Salvarsan

  • Recognized as the first chemical compound successfully used as an antimicrobial.

  • Inventor: Paul Ehrlich.

  • Usage: Treatment of syphilis; it was the 606th tested compound.

• Prontosil Dye

  • Effectiveness: Effective against streptococcal infections but ineffective in vitro.

  • Mechanism: Enzymes in animal blood convert prontosil into sulfonamide molecules, which act as competitive inhibitors of para-aminobenzoic acid (PABA).

• Alexander Fleming's Discovery

  • Observed that Staphylococcus colonies were not growing near mold, which revealed bactericidal activity.

  • Identified the mold as Penicillium, leading to the discovery of penicillin.

Penicillin and Its Development

Purification and Testing

• Ernst Chain and Howard Florey

  • Successfully purified penicillin for the first time.

  • In 1941, tested on a police officer with a life-threatening Staphylococcus aureus infection.

  • Initial treatment was effective but supply ran out resulting in patient death.

  • Upon adequate supply, subsequent treatments led to full patient recovery.

  • Mass production initiated during WWII for treating wounded soldiers.

Features of Antimicrobial Drugs

• Source: Derived primarily from soil organisms including:

  • Bacterial species such as Streptomyces and Bacillus.

  • Fungal species such as Penicillium and Cephalosporium.

• Production Process:

  • Strain inoculation into a broth medium; incubated to max concentration; extracted and purified.

  • Alteration for new characteristics gives rise to semi-synthetic drugs.

Principles of Antimicrobial Therapy

• The principal objective is selective toxicity which means:

  • Administering a drug that causes greater harm to microbes than to the patient.

  • This principle is challenging to achieve.

• Chemotherapeutic agents classification includes:

  • Origin, range of effectiveness, whether naturally or chemically synthesized.

Characteristics of Ideal Antimicrobial Drugs

• Selectively Toxic: Only harms the microbe without harming the host.

• Microbicidal: Preferably kills microbes rather than inhibiting their growth (microbistatic).

• Solubility: Should remain effective even when diluted.

• Potency Duration: Must remain effective long enough without degradation.

• Resistance: Should not foster the development of antimicrobial resistance.

• Activity Complementation: Should assist the host's immune response.

• Field Delivery: Should be deliverable to the infection site effectively.

• Cost-effective: Should be affordable.

• Safety: Should not cause severe allergic reactions or predispose to other infections.

Pharmacokinetics of Antimicrobial Drugs

• Drug Distribution, Metabolism, and Excretion:

  • Toxicity: Is evaluated in relation to the drug's therapeutic index, calculated as the lowest dose toxic to patients divided by the effective therapeutic dose.

  • Half-life: The time for the body to eliminate half the original serum drug dose, determining dosage frequency.

  • Patients with liver or kidney impairment may excrete drugs slower, necessitating dosage adjustments.

Effects of Antimicrobial Combinations

• Some combinations exhibit antagonistic effects:

  • E.g., bacteriostatic drugs that inhibit cell division may interfere with bactericidal drugs that kill dividing cells.

• Some combinations are synergistic, enhancing each other’s effects.

• Others may be additive, having a cumulative effect.

Adverse Effects of Antimicrobial Drugs

• Allergic Reactions: Particularly drugs like penicillin can cause life-threatening allergies.

• Toxic Effects: Examples include:

  • Aplastic anemia: a condition where the body fails to produce sufficient red and white blood cells.

  • Dysbiosis: Suppression of normal flora leading to opportunistic infections and antibiotic-associated colitis.

• Antimicrobial Resistance: This occurs when microorganisms become resistant to antibiotics either innately or adaptively.

Mechanisms of Action of Antibacterial Drugs

Targeted Structures and Processes in Bacteria

• Inhibition of:

  • Cell Wall Synthesis:

  • Unique to bacteria, targeting peptidoglycan.

  • Drugs include: β-lactams (penicillin, cephalosporin), vancomycin, bacitracin.

  • Protein Synthesis:

  • Depending on prokaryotic ribosome structure; targeted by aminoglycosides, tetracyclines, macrolides, chloramphenicol.

  • Nucleic Acid Synthesis:

  • Targeted by fluoroquinolones and rifamycins.

  • Metabolic Pathways:

  • Sulfonamides and trimethoprim inhibit folic acid production; critical since humans cannot synthesize their own folic acid.

  • Cell Membrane Integrity:

  • Disrupted by antibiotics such as polymyxin.

Specific Types of Antibacterial Action

Inhibition of Cell Wall Synthesis

• Peptidoglycan: Unique construction in bacterial cell walls.

• Safety: High therapeutic index for these drugs due to targeting bacterial cell wall synthesis which does not harm human cells.

• Drugs and Classes:

  • β-lactam Drugs: Penicillin and cephalosporins (competitively inhibit enzymes for peptide bridge formation).

  • Vancomycin: Effective against Gram-positive infections, generally administered intravenously due to poor absorption.

  • Bacitracin: Used solely for topical applications due to toxicity.

Mechanisms Specifically Targeting Protein Synthesis

• Key Classes:

  • Aminoglycosides: (e.g., gentamicin) may cause nephrotoxicity with extended use.

  • Bind to ribosome distorting its function, blocking translation initiation.

  • Tetracyclines: (e.g., doxycycline) effective against both Gram-positive and Gram-negative.

  • Can stain teeth if used in childhood and face resistance issues.

  • Macrolides: (e.g., erythromycin) prevent protein synthesis; an alternative for penicillin allergy patients.

  • Chloramphenicol: Broad-spectrum, reserved for severe infections due to aplastic anemia risks.

Antimicrobial Drugs Targeting Nucleic Acid Synthesis

• Fluoroquinolones: Disrupt DNA supercoiling, examples include ciprofloxacin and moxifloxacin.

• Rifamycins: Inhibit RNA polymerase action, effective against Mycobacterium tuberculosis.

Antimicrobial Drugs Targeting Metabolic Pathways

• Sulfonamides and Trimethoprim:

  • Inhibit folic acid production; essential since humans intake folate from diet.

Antimicrobial Drugs Altering Cell Membranes

• Polymyxin B: Affects Gram-negative bacteria by altering membrane permeability, usually limited to topical use.

Susceptibility Testing for Antimicrobial Drugs

Traditional Methods

• Kirby-Bauer Disc Diffusion Test:

  • Standard inoculation of bacterial strain on media with drug-impregnated discs; measured by zones of inhibition.

• E Test:

  • Uses gradient antibiotic strips to determine minimum inhibitory concentration based on tear-drop shaped zones.

Understanding Drug Resistance

Mechanisms of Resistance

• Can be intrinsic (such as innate characteristics) or acquired (via mutations or gene transfer).

• Resistance patterns caused by misuse or overuse of antimicrobials.

• Examples include:

  • Staphylococcus aureus: Evolution from 3% resistance to over 90% resistance against penicillin.

  • Enterococci: Naturally resistant to several antimicrobial agents.

  • Mycobacterium tuberculosis: Commonly shows spontaneous mutations, complicating treatment.

• Emerging resistant strains (e.g., MRSA) raising healthcare treatment challenges.

Addressing Drug Resistance

Combination Therapy

• Using multiple antibiotics reduces likelihood of resistance development.

• Physician Responsibilities:

  • Educate on proper antibiotic prescribing.

• Patient Responsibilities:

  • Follow prescription instructions meticulously to avoid resistance.

Mechanisms of Action for Antiviral Drugs

• Effective only against replicating viruses targeting:

  • Entry, viral uncoating, nucleic acid synthesis, assembly, and release.

• Target/Drug Examples:

  • Entry Inhibitors: Enfuvirtide, Maraviroc.

  • Viral Uncoating Inhibitors: Amantadine and rimantadine.

  • Nucleic Acid Synthesis Inhibitors: Nucleoside analogs such as acyclovir and zidovudine.

  • Protease and Neuraminidase inhibitors: Essential for assembly and release processes in viral replication.

Mechanisms of Action of Antifungal Drugs

• Primary Target: Ergosterol in fungal plasma membranes.

• Classes include Polyenes and Azoles, as well as targets for cell wall synthesis and nucleic acid synthesis.

• Challenges lie in targeting eukaryotic pathogens without harming human cells.

Alteration of Normal Flora by Antimicrobials

• Antimicrobials can disrupt the balance of normal flora leading to opportunistic infections.

Reasons Antimicrobial Treatments May Fail

• Ineffective delivery of drug to the infected site.

• Presence of resistant strains not identified in sensitivity tests.

• Polymicrobial infections with resistant pathogens.