L-21 Cell Wall Synthesis Inhibitors 3

Cell Wall Synthesis Inhibitors (Part III): Miscellaneous Inhibitors

• Vancomycin (Vancocin, Vancoled):

  • A tricyclic glycopeptide used orally and parenterally
  • Effective against methicillin-resistant staphylococcal infections and sepsis or endocarditis caused by Staphylococcus
  • Acts by inhibiting the synthesis of cell wall phospholipids and peptidoglycan polymerization by binding to D-alanyl-D-alanine cell wall precursors
  • Restricted to serious infections caused by beta-lactam-resistant Gram-positive bacteria (e.g., Streptococcus and Staphylococcus)
  • Used in enterococcal infections synergistically with aminoglycosides for better bactericidal effect (especially E. faecium and E. faecalis)
  • Used in Clostridium difficile-induced colitis (orally)
  • Also used prophylactically in dental surgeries involving prosthetic devices
  • Resistance is plasmid-mediated
  • Administered intravenously (slow I.V) in systemic infections
  • Excretion is primarily via glomerular filtration (more than 90%)
  • Orally administered for antibiotic-induced pseudomembranous colitis
  • Adverse effects include fever, chills, phlebitis, and mild ototoxicity and nephrotoxicity (risk increased with concurrent aminoglycoside use)
  • "Red man" or "red neck" syndrome (histamine release-induced flushing) is a common adverse reaction

• Fosfomycin (Phosphonomycin, Monurol):

  • Inhibits cell wall synthesis at a very early stage
  • An analog of phosphoenolpyruvate, inhibiting enolpyruvate transferase
  • Prevents the formation of N-acetyl muramic acid
  • Effective against both Gram-positive and Gram-negative organisms
  • Approved for single, oral dose (3 grams) treatment of uncomplicated urinary tract infections (UTIs) in women
  • Safe during pregnancy

• Bacitracin:

  • A mixture of polypeptides inhibiting cell wall synthesis
  • Active against a variety of Gram-positive cocci and bacilli
  • Primarily used topically due to significant nephrotoxicity if administered systemically (proteinuria, hematuria, nitrogen retention)
  • Poorly absorbed, resulting in localized antibacterial activity without significant systemic toxicity
  • Often combined with polymyxin and neomycin in ointment formulations for dermatologic and ophthalmic infections
  • Can be employed in irrigation solutions for joints, wounds, and pleural cavities

• Polymyxin B, Polymyxin E (Colistin):

  • Peptides active against Gram-negative bacteria, but restricted to treating only Gram-negative infections
  • Due to nephrotoxicity, only Polymyxin B is commonly used in the USA; Polymyxin B and E are used in other regions
  • Bactericidal, disrupting bacterial cell membranes by attaching to them via cationic interactions
  • Disrupts phospholipid-based membranes, also inactivating endotoxins
  • Gram positives (e.g. Proteus, Neisseria) show resistance
  • Primarily used topically and ophthalmically due to high nephro- and neurotoxicity
  • Often combined with other antibiotics like Neomycin and Bacitracin for skin infections
  • Rarely associated with local reactions or hypersensitivity

• Cycloserine (Seromycin):

  • Water-soluble antibiotic readily absorbed orally
  • Active against many Gram-positive and Gram-negative bacterial strains
  • Primarily used to treat tuberculosis caused by M. tuberculosis strains resistant to first line agents
  • Structural analog of D-alanine, inhibits enzymes (alanine racemase and alanine synthetase) converting L-alanine to D-alanine in the peptidoglycan synthesis process
  • Widely distributed in tissues, specifically in the case of Mycobacteria
  • Excreted in active form via the urine
  • Adverse effects include central nervous system (CNS) toxicity: Headaches, tremors, psychosis, and convulsions.

• Daptomycin (Cubicin):

  • Bactericidal lipopeptide antibiotic
  • Disrupts bacterial cell membranes and inhibits protein and DNA synthesis
  • Used for complicated skin and skin structure infections and bacteremia caused by Staphylococcus aureus, including endocarditis
  • Action similar to linezolid and quinupristin/dalfopristin (for Gram-positive resistant organisms, like MRSA and VRE)
  • Inactivated by pulmonary tissue, not used for pneumonia treatment

• Telavancin (Vibativ):

  • Bactericidal lipoglycopeptide antibiotic structure similar to vancomycin
  • Dual mechanism of action similar to daptomycin and vancomycin
  • Used for treating complicated skin and skin structure infections and nosocomial and ventilator-associated pneumonia caused by MRSA
  • Can cause renal impairment and interfere with anticoagulation tests; contraindicated in pregnancy; associated with some cardiac abnormalities