Pharmacology II: Cell Wall Inhibitors I

ESKAPE Pathogens

• ESKAPE refers to pathogens that escape antibacterial effects.
• Key ESKAPE pathogens include:
  • Enterococcus faecium (VRE)
  • Staphylococcus aureus (MRSA)
  • Klebsiella pneumoniae (carbapenem-resistant)
  • Acinetobacter baumannii
  • Pseudomonas aeruginosa (fluoroquinolone-resistant, multidrug-resistant)
  • Enterobacter species
  • Multidrug-resistant Escherichia coli

Antibacterial New Molecular Entities

• Recent decline in the development of antibacterial new molecular entities (NMEs).
• Various organizations contribute to the research and development of NMEs, with some entering and exiting the field.

Cell Wall Structure

• Gram-positive bacteria have a thicker peptidoglycan layer, easily penetrated by penicillins.
• Gram-negative bacteria possess an outer lipopolysaccharide membrane, blocking water-soluble penicillins.
• Penicillin-binding proteins (PBPs) are essential for cross-linking peptidoglycan in bacterial cell walls.

Mechanism of Action of Penicillins

• Penicillins disrupt peptidoglycan cross-linking, leading to weakened cell walls and potential lysis via osmotic pressure or autolysins.
• Effective only against rapidly growing organisms with peptidoglycan cell walls; ineffective against mycobacteria, protozoa, fungi, and viruses.

Penicillin Structure & Mechanism

• Bacterial cell walls consist of N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM).
• NAM subunits are cross-linked by PBPs; penicillin covalently binds to serine residues in PBPs, blocking their function.

Antibacterial Spectrum of Penicillins

• Natural penicillins (Penicillin G and V) are susceptible to beta-lactamases; Penicillin V has poor oral absorption.
• Antistaphylococcal penicillins (Methicillin, Nafcillin) target penicillinase-producing staphylococci but are not clinically used due to toxicity.
• Extended-spectrum penicillins (Ampicillin, Amoxicillin) are more effective against gram-negative bacteria and can prevent bacterial endocarditis.
• Beta-lactamase inhibitors (Clavulanic acid, Sulbactam) enhance the efficacy of ampicillin and amoxicillin against resistant strains.

Antipseudomonal Penicillins

• Piperacillin and Ticarcillin are effective against many gram-negative bacilli but ineffective against Klebsiella due to penicillinase production.

Resistance Mechanisms

• Major causes of resistance include:
  • Inactivation by beta-lactamases.
  • Modification of target PBPs.
  • Impaired drug penetration to target PBPs.
  • Drug efflux mechanisms.

Pharmacokinetics of Penicillins

• Common administrations include:
  • Ampicillin and sulbactam, ticarcillin and clavulanic acid, piperacillin and tazobactam administered IV or IM.
  • Oral options include Penicillin V and Amoxicillin.
  • Long-acting forms like Procaine penicillin G and Benzathine penicillin G provide sustained low-level circulation.

Adverse Reactions

• Penicillins are generally non-toxic; however, adverse reactions may include:
  • Hypersensitivity reactions, from rashes to anaphylaxis.
  • Disruption of intestinal flora leading to diarrhea and potential pseudomembranous colitis caused by Clostridium difficile.
• Cross-allergic reactions occur among beta-lactam antibiotics.

This quiz focuses on Cell Wall Inhibitors and the notable 'ESKAPE' pathogens that exhibit resistance to antibacterial treatments. It will cover the characteristics of these bacteria and their significance in pharmacology. Prepare to test your knowledge on crucial pharmacological concepts!