Antimicrobial Drugs and Resistance

Definition of Spectrum Types:
  - Narrow-Spectrum:
    - Effective on a small range of cell types.
    - Example: Bacitracin
      - Mechanism: Blocks elongation of peptidoglycan.
      - Effect: Active against gram-positive bacteria only, no effect on gram-negative  -        Medium-Spectrum:
    - Effective on both gram-positive and gram-negative bacteria, but not all types.        - Broad-Spectrum:
    - Effective on most gram-negative and gram-positive bacteria, rickettsias, mycoplasmas, and spirochetes.
    - Example: Tetracycline
      - Mechanism: Blocks the attachment of charged aminoacyl-tRNA to the A site of the ribosome.

Inhibition of Cell Wall Synthesis:
  - Examples:
    - Penicillins
    - Cephalosporins
Disruption of Cell Membrane Structure/Function:
- Example: Polymyxins
Inhibition of DNA and RNA Synthesis:
- Examples: Chloroquine, nucleotide analogues.
Inhibition of Protein Synthesis:
- Mechanism: React with the ribosome-mRNA complex.
- Examples: Aminoglycosides, Tetracycline.
Interference with Metabolic Pathways:
- Mechanism: Mimic normal substrate of an enzyme, competitive inhibition.
- Examples: Sulfonamides, trimethoprim (interfere with folate metabolism necessary for DNA synthesis).

Antimicrobial	Action	Spectrum
Penicillins	Inhibits cell wall synthesis	Narrow spectrum – Gram positive
Cephalosporins	Inhibits cell wall synthesis	Broad spectrum
Vancomycin	Cell wall inhibitor	Narrow spectrum
Bacitracin	Cell wall inhibitor	Narrow spectrum
Isoniazid	Cell wall synthesis inhibitor	Narrow spectrum
Polymyxins	Damage bacterial cell membranes	Narrow spectrum - Gram negative
Fluoroquinolones	Inhibits DNA topoisomerase	Broad spectrum
Rifampin	Inhibits RNA synthesis	Broad spectrum
Aminoglycosides	Impairs ribosome function	Broad spectrum
Tetracyclines	Blocking protein synthesis	Broad spectrum
Chloramphenicol	Block peptide bond formation	Broad spectrum
Macrolides	Attach to 50S or 30S ribosome subunit	Broad spectrum
Sulfonamides	Block folic acid synthesis	Broad spectrum

Antimicrobial	Action
Macrolide polyenes	Bind to membranes (ergosterol) causing loss of selective permeability.
Azoles	Inhibit ergosterol and cell membrane synthesis.
Griseofulvin	Interferes with microtubule function inhibiting mitosis.
Flucytosine	Nucleotide analogue affecting nucleic acids.

Quinine:
- Oldest antimalarial drug; no longer recommended due to toxicity.
- Mechanism of action unclear; similar lower-toxicity derivatives developed in its place.

Metronidazole:
- Inhibits nucleic acid synthesis by disrupting DNA of microbial cells.
- Commonly used for infections caused by Giardia and Entamoeba histolytica.

Helminthes:
- Non-microscopic organisms including flukes, tapeworms, roundworms.
Examples of Anthelminthic Drugs:
  - Mebendazole and Thiabendazole:
    - Action: Broad-spectrum antiparasitic drugs blocking glucose uptake.   - Pyrantel and Piperazine:
    - Action: Paralyze muscles of intestinal roundworms.

Major Modes of Action:
- Barring penetration of the virus into the host cell. - Blocking replication, transcription, and/or translation of viral genetic material. - Preventing normal maturation of viral particles.

Antiviral	Works by…	Inhibits…
Acyclovir, Valacyclovir, Famciclovir, Ribavirin	Inhibiting DNA synthesis – nucleotide analogs	Herpes viruses
Tamiflu	Blocks neuraminidase; Stops uncoating	Influenza A virus
Reverse Transcriptase Inhibitors, Protease Inhibitors, Integrase Inhibitors, Entry/Fusion Inhibitors	Given as a cocktail	HIV
Interferon (Cytokines)	Modulate functions of the immune system	All viruses in general

Mechanisms of Drug Resistance:
- Induction of alternate enzymes that can inactivate the drug. - Decreased or eliminated permeability/uptake of the drug into the bacterium. - Special drug transport pumps removing the drug from the microbe. - Decrease in binding sites for the drug regarding number or affinity. - Shutdown of an affected metabolic pathway or the use of an alternate pathway.

Factors Include:
- Patient compliance (or lack thereof) - Physician knowledge and testing - Global antibiotic availability and travel - Use of antibiotics in animal feed.

Toxicity to Organs:
- Types include; hepatotoxic, nephrotoxic, hemotoxic, neurotoxic.
Allergic Response to Drugs:
- Drugs may act as antigens causing allergic reactions.
Suppression and Alteration of Microflora by Antimicrobials:
- Leads to diarrhea and superinfections due to destruction of beneficial resident species.

Key Factors to Consider:
- The nature of the microorganism causing the infection. - Sensitivity of the microorganism to various drugs. - Medical condition of the patient. - Importance of rapid identification of the infectious agent and relevant epidemiological statistics.
Testing for Drug Susceptibility:
- Kirby-Bauer Procedure: a disk diffusion method. - Minimum Inhibitory Concentration (MIC): The smallest concentration of drug that inhibits microbial growth.

Reasons for Drug Failure Despite Successful In Vitro Tests:
- Inability of the drug to diffuse throughout the body. - Presence of resistant microorganisms. - An infection caused by multiple pathogens.
Therapeutic Index (TI):
  - Definition: The ratio of the toxic dose of the drug to its minimum effective dose.
  - Calculation:
     $ext{Therapeutic Index (TI)} = rac{ ext{Toxic Dose}}{ ext{MIC}}$