Antibiotics Summary

Antibiotics

Definition

• An antibiotic is a substance produced by a living microorganism to kill or inhibit the growth of another living microorganism.

Classification of Antibiotics

According to Mechanism of Action:

• Bactericidal:
  • β-Lactam antibiotics
  • Quinolones
  • Aminoglycosides
  • Rifampicin
• Bacteriostatic:
  • Sulfonamides
  • Chloramphenicol
  • Tetracyclines
• Bacteriostatic and Bactericidal:
  • According to drug concentration, e.g., erythromycin

According to Spectrum:

• Narrow Spectrum:
  • Penicillins
  • Erythromycin
  • Streptomycin
  • Sulfonamides
• Broad Spectrum:
  • Chloramphenicol
  • Tetracyclines

According to Site of Mechanism of Action:

• Inhibit Synthesis of Bacterial Cell Wall:
  • β-Lactam antibiotics
  • Vancomycin
  • Bacitracin
  • Teicoplanin
• Increase Permeability of Cytoplasmic Membrane → Cell Damage:
  • Amphotericin
  • Nystatin
• Inhibition of Protein Synthesis:
  • Formation of mRNA (↓ RNA polymerase enzyme): e.g., Rifampicin.
  • Binding with 30S ribosomal subunit of bacteria: e.g., Aminoglycoside, tetracycline.
  • Binding with 50S ribosomal subunit of bacteria: e.g., chloramphenicol, erythromycin.
• Inhibition of Nucleic Acid Metabolism:
  • Folate Antagonists:
    • Compete with PABA e.g., sulfonamides.
    • ↓ dihydrofolate reductase enzyme: as Trimethoprim
  • ↓ DNA:
    • Quinolones (↓ DNA gyrase enzyme)
    • Metronidazole & Chloroquine, Griseofulvin
  • ↓ RNA:
    • e.g.: Rifampicin

Mechanism of Action Summary (Based on Site):

• Cell Wall Synthesis Inhibitors:
  • Beta Lactams (Penicillins, Cephalosporins, Carbapenems, Monobactams)
  • Vancomycin
  • Bacitracin
  • Cycloserine
• Folate Synthesis Inhibitors:
  • Sulfonamides (compete with PABA)
  • Trimethoprim (inhibits dihydrofolate reductase)
• Nucleic Acid Synthesis Inhibitors:
  • Quinolones (inhibit DNA Gyrase)
  • Rifampin (inhibits RNA Polymerase)
  • Actinomycin
  • Ciprofloxacin
  • Novobiocin
  • Streptovaricins
• Protein Synthesis Inhibitors:
  • 30S Subunit:
    • Tetracyclines
    • Aminoglycosides (Streptomycin, Gentamicin, Kanamycin, Amikacin)
    • Spectinomycin
  • 50S Subunit:
    • Macrolides (Erythromycin)
    • Clindamycin
    • Linezolid
    • Chloramphenicol
    • Streptogramins
    • Lincomycin
  • tRNA:
    • Mupirocin
    • Puromycin
• Cell Membrane Disruptors:
  • Polymyxins
  • Daptomycin

Inhibitors of Bacterial Cell Wall Synthesis – β-Lactam Antibiotics

• Penicillins
• Cephalosporins
• Monobactams e.g., aztreonam.
• Carbapenems e.g., imipenem-meropenem.

Penicillins:

• Mechanism of Action:
  • Bactericidal
  • Inhibit Transpeptidase enzyme (Penicillin-Binding-Protein or PBP), which is responsible for cross-linking of peptidoglycans → inhibiting Cell Wall Synthesis.
  • Activate Autolysins, leading to antibacterial activity.
  • D-Ala-D-Ala structural mimics: ∞ ∞
• Selectivity
• Spectrum
• Resistance

β-Lactam Mechanism of Action

• β-lactams bind to transpeptidase active site
• Block of transpeptidase activity interrupts cross-linking & cell wall synthesis

Antibiotic Resistance

• Definition:
  • Bacteria are said to be resistant to an antibiotic if the maximal level of that antibiotic that can be tolerated by the host does not halt their growth, OR,
  • If bacteria are not inhibited by usually achievable systemic concentration of an antibiotic with normal dosage schedule and/or Fall in the minimum inhibitory concentration (MIC).
    Equation for Antibiotic Resistance (DR)

Antibiotic Resistance (DR) = MIC/MCC < Toxic Plasma Concentration

• Cross-resistance:
  • Germs that develop resistance to one antibiotic have the ability to develop resistance to another antibiotic.

Members of Penicillins

• Natural Penicillins:
  • Acid Labile
    • Benzyl Penicillin (Penicillin G)
  • Acid Resistant
    • Penicillin V (Phenoxymethyl penicillin)
• Semisynthetic Penicillins:
  • Penicillinase-resistant penicillins
    • Methicillin
    • Oxacillin
    • Cloxacillin
  • Extended-spectrum penicillins
    • Aminopenicillins (Ampicillin, Bacampicillin, Amoxicillin)
    • Carboxypenicillins (Carbenicillin, Carbenicillin indanyl, Carbenicillin phenyl, Ticarcillin)
    • Ureidopenicillins (Piperacillin, Mezlocillin)
    • Mecillinam
    • Amdinocillin
  • B-Lactamase Inhibitors (Clavulanic Acid, Sulbactam, Tazobactam) - Used in combination with penicillins.

Key Characteristics of Penicillin Members

1. Benzyl Penicillin (Penicillin G):
   • Side effects: a, b, c & d
2. Long Acting Penicillins:
   • Side effects: b, c & d
3. Acid Resistant Penicillins:
   • Side effects: a, c & d
4. β-Lactamase (Penicillinase) Resistant:
   • Side effects: a, b & d
5. Acid & B-Lactamase Resistant Penicillins:
   • Oxa
6. Broad Spectrum Penicillins:
   • Amino-penicillin
7. Extended Spectrum (Antipseudomonal) PenicillinsKey to Side Effects
   • a. Short duration
   • b. Acid sensitive
   • c. Lactamase (Penicillinase) sensitive
   • d. Narrow spectrum

B-Lactamase Inhibitors

• clavulanic acid
• sulbactam
• tazobactam

Pharmacokinetics of Penicillins

• Absorption
• Distribution
• Not teratogenic
• Metabolism
• Excretion
  • Renal

Therapeutic Uses of Penicillins

• Treatment and Prophylaxis of:
  • Pharyngitis
  • Tonsillitis
  • Scarlet Fever
  • Endocarditis
  • Pneumococcal Infections
  • Staphylococcal Infections
  • Diphtheria
  • Anthrax
  • Syphilis

Toxicity of Penicillins

• Itching
• Skin rash
• Urticaria
• Jarisch-Herxheimer Reaction
  1. Treatment with antibiotic
  2. Sudden release of bacterial products (spirochetal & other bacteria)
  3. Fever, constitutional symptoms
  • Management: Supportive care
• Angioedema

Cephalosporins

• Bactericidal effect
• Inhibition of Peptidoglycan synthesis leading to Failure of cross linkage
  Effect on Transpeptidase (PBP)

Cephalosporins Pharmacokinetics:

• Most cephalosporins do not penetrate the CSF; third-generation agents achieve therapeutic levels in CSF
• Ceftriaxone appears in bile
• Mostly unchanged drug appears in urine
• Administered via I.V. or I.M.

Cephalosporin Generations:

Uses of Cephalosporins:

• Broad-spectrum antibiotics derived from Cephalosporium acremonium fungus
• Treat bacterial infections
  • Meningitis
  • Pneumonia
  • Urinary Tract Infections
  • Sepsis

Adverse Effects of Cephalosporins:

• Cross-allergy with penicillin (10%)
• GIT upset
• Ceftriaxone + Calcium interaction
• Disulfiram-like action

Monobactams

• Aztreonam
• β-Lactamase resistant
• Narrow spectrum
• There is NO cross-allergy with penicillins

Carbapenems (Imipenem, Meropenem)

• Bactericidal
• Very wide spectrum
• Imipenem + Cilastatin = Tienam
• Adverse effects
  • Allergy
  • Seizures
  • GIT upsets

Comparison of Imipenem and Meropenem:

Vancomycin

• Glycopeptide
• Inhibits early steps of Cell wall synthesis → Peptidoglycan polymerization → Bactericidal.
• Gram +ve organisms including MRSA, C. difficile & Enterococci.
• Adverse Effects:
  • Red man syndrome
  • Ototoxic
  • Nephrotoxic

Mechanism:

• Inhibits Transglycosylases

Vancomycin Side Effects

• Mnemonic: Vancomycin can cause A TON of Red man syndrome if infused too fast
  • Thrombophlebitis
  • Ototoxicity
  • Nephrotoxicity
  • Red man syndrome
    • Red man syndrome - IgE mediated (angioedema is very rare)
  • Drug fever
  • Fever