Lec 21. Cell Wall Synthesis Inhibitors III, Dr. Panavelil PDF

Cell Wall Synthesis Inhibitors Part III: Miscellaneous Cell Wall Synthesis Inhibitors Thomas A. Panavelil, Ph.D., M.S., M.B.A. VANCOMYCIN (Vancocin, Vancoled): Vancomycin is a tricyclic glycopeptide used orally and parenterally. Use: Vancomycin is a good drug against methicillin-resistant stap...

Cell Wall Synthesis Inhibitors Part III: Miscellaneous Cell Wall Synthesis Inhibitors Thomas A. Panavelil, Ph.D., M.S., M.B.A. VANCOMYCIN (Vancocin, Vancoled): Vancomycin is a tricyclic glycopeptide used orally and parenterally. Use: Vancomycin is a good drug against methicillin-resistant staphylococcal infections. The main indication of parenteral vancomycin is sepsis or endocarditis caused by staphylococcus. Action: Inhibits synthesis of cell wall phospholipids and peptidoglycan polymerization by binding to D-alanyl-D-alanine cell wall precursors. Use of vancomycin is restricted to serious infections by beta-lactam resistant gram-positive (Eg. Strep. and Staph. infections) microorganisms. In enterococcal infections, aminoglycosides are given synergistically for bactericidal effect (caused by E. faecium and E. faecalis). Vancomycin is used in colitis caused by Clostridium difficile ORALLY (anaerobic gram-positive rod). Prophylactically in dental surgeries in prosthetic device implanted patients. Resistance: Plasmid mediated. Kinetics: Parenteral administration is by slow I.V (Vancocin HCl) in systemic infections. More than 90% is excreted by glomerular filtration. Given orally in case of antibiotic induced pseudomembranous colitis (PMC) due to C. difficile. Adverse: Fever, chills, phlebitis etc. Irritating to tissue. Ototoxicity and nephrotoxicity are mild with current preparations but simultaneous use of aminoglycosides increases the risk. Among the more common reactions is the so-called “red man” or “red neck” syndrome that is caused by flushing due to histamine release. FOSFOMYCIN (Phosphonomycin, Monurol): Inhibits very early stage of cell wall synthesis. An analogue of phosphoenolpyruvate that inhibits enolpyruvate transferase, thus inhibiting formation of N-acetyl muramic acid. Works well against gram-positive and gram-negative organisms. In the United States it is approved as a single, oral dose (3 grams) for treatment of uncomplicated UTI in women. It is safe during pregnancy. BACITRACIN: Mixture of polypeptides that inhibit cell wall synthesis. It is active against a variety of gram- positive cocci and bacilli. It is markedly nephrotoxic, if administered systemically, producing proteinuria, hematuria, and nitrogen retention. Therefore, it is used only topically. It is absorbed poorly therefore topical application results in local antibacterial activity without significant systemic toxicity. Bacitracin in an ointment base is often combined with polymyxin and neomycin. Used in dermatologic and ophthalmic infections. Solutions of bacitracin are sometimes employed for irrigation of joints, wounds and pleural cavity. POLYMYXIN B, POLYMYXIN E (Colistin) Polymyxins are peptides that are active against gram negative bacteria and are restricted to treating gram-negative bacterial infections. Due to their nephrotoxicity, only Polymyxins B and E are used. Only Polymyxin B is used in the USA. Polymyxin E is otherwise known as Colistin. Polymyxins are cationic basic peptides. Action: Polymyxins are bactericidal for many gram-negative rods including Pseudomonas in concentration 1-5 ug/ml. Being cationic detergents, they attach to and disrupt bacterial cell membranes. Polymyxins are surface-active amphipathic agents (with lipophilic and lipophobic groups). They interact with phospholipids and disrupt the cell membranes. They also bind and inactivate endotoxins. Gram-positive organisms proteus and Neisseria are resistant. Toxicity: Due to availability of several alternative antimicrobials, Polymyxins are not used for systemic administration because of their high nephrotoxicity, neurotoxicity and poor tissue distribution. Use: Polymyxins are restricted to ophthalmic, optical and topical use. Corneal ulcers and external otitis caused by Pseudomonas is treated with polymyxins. Combinations of Neomycin, Polymyxins and Bacitracin are used for skin infections. Local reactions and hypersensitivity are rarely observed. CYCLOSERINE (SEROMYCIN) Cycloserine is a water-soluble antibiotic readily absorbed upon oral administration. Cycloserine is active against many gram-positive and gram-negative strains. Cycloserine is used almost exclusively to treat tuberculosis caused by M. tuberculosis resistant to first line agents. Cycloserine is a structural analogue of D-alanine, thus inhibits of D-alanine into peptidoglycan (inhibits enzymes alanine racemase that converts L-alanine to D-alanine and alanine synthetase). Cycloserine inhibits many strains of mycobacteria. The drug gets widely distributed in tissues. IT is used orally as 250 mg capsules. Most of the drug is excreted in active form into the urine. Adverse: Cycloserine can cause CNS toxicity with headaches, tremors, psychosis and convulsions. Daptomycin  DAPTOMYCIN (Cubicin) Daptomycin is a bactericidal lipopeptide antibiotic. MOA: Disrupts the membrane, inhibits also protein & DNA synthesis. Daptomycin is used for treating complicated skin and skin structure infections and bacteremia caused by S. aureus, including infective endocarditis. Its action resembles linezolid and quinupristin/dalfopristin, for treating infections caused by resistant gram-positive organisms, including MRSA and vancomycin-resistant enterococci (VRE). Daptomycin is inactivated by in pulmonary tissue and is not used in the treatment of pneumonia.  TELAVANCIN (Vibativ) Telavancin is bactericidal lipoglycopeptide antibiotic and is similar to vancomycin in structure. Telavancin has dual mechanism of action similar to that of daptomycin plus vancomycin. It is classified as advanced drug in treating complicated skin and skin structure infections, caused by MRSA, and for nosocomial hospital acquired and ventilator-associated bacterial pneumonia (HABP/VABP). The drug causes renal impairment and interferes with anticoagulation tests. It is contraindicated in pregnancy and has caused some cardiac abnormalities.