Antibiotics

Antibiotics Summary

Antibiotics are part of the Antibacterial Agents (Etiotropic Agents)
They can induce selection of Resistant Bacteria

Most Antibiotics are produced by bacteria (to compete against other bacteria), then fungi (also to compete against bacteria), then humans (laboratory synthesis)

Drugs:

• Bactericidal Agents:
  • Time Dependent:
    • Penicillins (β-Lactams)
    • Cephalosporins (β-Lactams)
    • Nitrofurans
    • Potentiated Sulfonamides (PSA)
    • (Fosfomycin): AMEG A Banned
  • Concentration Dependent:
    • Aminoglycosides (Only Bactericidal Protein Synthesis Inhibitors - On 30S): except Spectinomycin
    • Fluoroquinolones
    • Nitroimidazoles
    • Polypeptide Antibiotics
    • Rifamycins
    • Aminocoumarins (Novobiocin)
• Bacteriostatic Agents:
  • Protein Synthesis Inhibitors:
    • On 30S:
      • Tetracyclines
      • (Spectinomycin)
    • On 50S: Cross resistance
      • Amphenicols
      • Macrolides
      • Lincosamides
      • Pleuromutilins
    • Others:
      • Fusidic Acid
      • Mupirocin
  • Folic Acid Pathway Inhibitors:
    • Sulfonamides
    • Diaminopyrimidines

Classification by AntiMicrobial ad hoc Expert Group AMEG (European Public Health Organism):

• A) Avoid:
  • Some substances are totally banned (Vancomycin, Linezolide, Piperacillin)
  • The allowed ones are only for non food producing animals (Rifampicin, Mupirocin)
• B) Restrict: Highest priority of the CIA group (of WHO nomenclature), most important Antibiotics in human medicine (mitigate the risk of selecting Resistant Bacteria by avoiding them in veterinary medicine)
  • Fluoroquinolones
  • 3rd Generation Cephalosporins and 4th Generation Cephalosporins
  • Colistin
• C) Caution: Antibiotics of this categories have alternatives in human medicine
  • Amoxicillin, Ampicillin when given with β-Lactamase Inhibitors
• D) Prudence: Should be used as first line treatment when possible
  • Amoxicillin, Ampicillin when given without β-Lactamase Inhibitors

Classification by origin:

• Natural: Naturally produced compounds
  • Penicillins (Antibiotics)
• Semisynthetic: Naturally produced compounds that are chemically modified/enhanced
  • Amoxicillin (Antibiotics)
• Synthetic: Fully engineered and laboratory created compounds
  • Sulfonamides (Etiotropic Agents)

Efficacy parameters:

• MIC Minimum Inhibitory Concentration: Lowest concentration that effectively inhibits the growth of a bacteria strain
  • MIC is used instead of Effective Dose ED50 for Antibiotics
  • We use the MIC parameter even to describe properties of Bactericidal Agents (despite the fact that they are not only inhibitory but bactericidal)
• MBC Minimum Bactericidal Concentration: Lowest concentration that effectively kills 99.9% of bacteria
  • In the dilution methods, MBC/MIC is the lowest concentration of Antibiotics where we stop seeing bacteria (no growth / no turbidity)
  • Generally MBC ≤ 4x MIC (So MBC is no bigger than 4 times MIC)
    • Under MIC there’s bacterial growth, at MIC we have no growth, if we increase the dose to MBC there is decrease (to complete elimination of the bacteria at MPC)
• MPC Mutation Prevention Concentration: Lowest (Yet relatively high) concentration of Antibiotics at which even Resistant Bacteria won’t grow
  • Above MPC dose, the Antibiotics is “safe” (if we disregard the toxicity risks) on the Resistant Bacteria mutants selection aspect
• MSW Mutant Selection Window: Antibiotics doses between MIC and MPC where the dose is strong enough to kill sensitive bacteria, but to weak to kill the Resistant Bacteria, so it can induce a selection process
  • Increasing dose: No bacteria are Killed (= No selection) < MIC < Only the Antibiotics sensitive bacteria are killed (= Selection risk) < MPC < All the bacteria are killed (= No selection)

Mode of action:

• Bactericidal Agents: Active ingredient kills the bacteria
  • After stopping the Antibiotics, the bacteria are dead so they won’t grow back
  • Time Dependent Bactericidal Agents Plasma Cmax should stay above MBC for as long as possible (generally over a week)
  • Concentration Dependent Bactericidal Agents Plasma Cmax should stay high (above 8-12x MIC for Fluoroquinolones generally)
  • AUC Area Under the Curve integates both concentration and time, it is useful for Antibiotics where both the time and concentration matter
• Bacteriostatic Agents: Active ingredient inhibits the growth of bacteria
  • After stopping the Antibiotics, the bacteria may grow back
    • Generally the Immune system eliminates the inhibited bacteria so they can’t grow back
      • It is preferable to use Bactericidal Agents for Immunocompromised patients as the bacteria can grow back
  • Bacteriostatic Agents have a Bactericidal Agents effect in some cases
• The mechanism of action (ex target 30S) doesn’t necessarily give the mode of action (if the Antibiotics is Bactericidal Agents or Bacteriostatic Agents)

PAE Post Antibiotic Effect:
Delayed antibacterial effect after the Plasma Cmax of the Antibiotics decreased below MIC

• Present in β-Lactams, Aminoglycosides, Fluoroquinolones

Combinations of Antibiotics:

• Synergistic: Both drugs target complementing structures
  • ex: AB1 targets 30S, and AB2 targets 50S subunits of the bacterial ribosome
  • ex: Penicillins (PBP) + Streptomycin (30S)
  • ex: Lincomycin (50S) + Spectinomycin (30S)
• Additive: Combination of drugs allows to have a wider coverage spectrum
  • ex: AB1 targets Gr+ bacteria, and AB2 targets Gr- bacteria
  • ex: Gentamicin (Aerobes) + Metronidazole (Anaerobes) used in systemic infections
• Antagonist: Doesn’t necessarily mean they neutralize each other’s effect, but it can be a combination that isn’t the most efficient
  • Bactericidal-Bacteriostatic: Some Bactericidal Agents only work against dividing bacteria, they are rendered useless if combined with Bacteriostatic Agents
  • Same target: Competition on the target, they can’t both act on the same site at the same moment, they are analogues and using both is redundant
    • ex: AB1 and AB2 both target the 50S subunit
      • ex: Erythromycin (50S) + Florfenicol (50S)

Very few Antibiotics are fit for Horses (Treatment of Horses Infections, most are deadly
Many antibiotics are banned for food producing animals (AMEG A completely banned)
There’s different Antibiotics resistance (Resistant Bacteria) depending on the treated animal species
Antibiotics medicated feed can include treatment for up to 2 weeks

Very few Antibiotics can treat Pseudomonas aeruginosa infections: Antibiotics Acting Against Pseudomonas spp

Alternatives to Antibiotics:

• Probiotics
• Phage Therapy
• Phytobiotics
• Organic Acids (Cleaning Agents)

Antibiotics are described by: Antibiotics Summary

• Structure
• Mechanism of action
• Mode of action
• Resistance
• Antibacterial spectrum
• Pharmacokinetics (ADME)
  • Absorption
  • Distribution
  • Metabolism
  • Excretion
• Side effects
• Indications