1. PHL 424 Antimicrobials 6 th Lecture By Abdelkader Ashour, Ph.D. Phone: 4677212Email: aeashour@ksu.edu.sa

2. Other Cell Wall or Membrane-active Agents, Vancomycin, Its structure

3. Other Cell Wall or Membrane-active Agents, Vancomycin  Vancomycin is poorly absorbed from the GIT  It can be administered orally to patients with pseudomembranous colitis, although metronidazole is preferred  Parenteral doses must be administered intravenously  Ninety percent of the drug is excreted by glomerular filtration. In the presence of renal insufficiency, unusual accumulation may occur  It should be used only to treat serious infections:  Management of infections due to methicillin-resistant staphylococci, including pneumonia & endocarditis  Management of severe staphylococcal infections in patients who are allergic to penicillins and cephalosporins  Management of known or suspected penicillin-resistant pneumococcal infections

4. Other Cell Wall or Membrane-active Agents, Vancomycin  Side Effects:  Hypersensitivity reactions e.g., macular skin rashes and anaphylaxis  Rapid I.V. infusion may cause erythematous or urticarial reactions, flushing, tachycardia and hypotension The extreme flushing that can occur is sometimes called "red-neck" or "red- man" syndrome This is not an allergic reaction but a direct toxic effect of vancomycin on mast cells, causing them to release histamine  Auditory impairment, sometimes permanent, may follow the use of this drug. Ototoxicity is associated with excessively high concentrations of the drug in plasma  Nephrotoxicity has become an unusual side effect when appropriate doses are used, as judged by renal function and determinations of blood levels of the drug Caution must be exercised when ototoxic or nephrotoxic drugs, such as aminoglycosides, are administered concurrently or in patients with impaired renal function

5. Inhibitors of bacterial protein synthesis, Overview  These agents are bacteriostatic, protein-synthesis inhibitors that target the ribosome  Examples: Chloramphenicol, macrolides, clindamycin, tetracyclines (A-site) (P-site) Chloramphenicol Θ Macrolides, clindamycin Θ Θ Tetracyclines

6. Inhibitors of bacterial protein synthesis, Chloramphenicol  It is an antibiotic produced by Streptomyces venezuelae  It is a potent inhibitor of microbial protein synthesis  MOA: It binds reversibly to the 50S subunit of the bacterial ribosome and thus inhibits the peptidyl transferase step of protein synthesis {i.e., it inhibits the transpeptidation reaction (1)} ……How?  It binds to the 50S ribosomal subunit at the peptidyltransferase site, thus the interaction between peptidyltransferase and its amino acid substrate cannot occur, and peptide bond formation is inhibited  It also can inhibit mammalian mitochondrial protein synthesis {mitochondrial ribosomes resemble bacterial ribosomes (both are 70S)}  The peptidyltransferase of mammalian mitochondrial ribosomes, but not of cytoplasmic ribosomes, is inhibited by chloramphenicol  inhibition of synthesis of proteins of the inner mitochondrial membrane  Mammalian erythropoietic cells are particularly sensitive to the drug  Much of the toxicity observed with this drug can be attributed to these effects

7. Inhibitors of bacterial protein synthesis, Chloramphenicol, contd.  Antimicrobial Actions:  It is a bacteriostatic broad-spectrum antibiotic that is active against both aerobic and anaerobic G+ve and G-ve organisms  It is active also against rickettsiae and mycoplasma  Haemophilus influenzae, Neisseria meningitidis and Bordetella pertussis are highly susceptible  Strains of S. aureus tend to be less susceptible  P. aeruginosa is resistant to even very high concentrations of the drug  Resistance:  It is usually caused by a plasmid-encoded acetyltransferase that inactivates the drug. Acetylated derivatives of chloramphenicol fail to bind to bacterial ribosomes  Resistance also can result from decreased permeability and from ribosomal mutation

8. Inhibitors of bacterial protein synthesis, Chloramphenicol, contd.  Pharmacokinetics  It is readily absorbed from the GIT  The parenteral formulation, chloramphenicol succinate, yields free chloramphenicol by hydrolysis, giving blood levels lower than those achieved with orally administered drug  After absorption, it is widely distributed in body fluids and readily reaches therapeutic concentrations in CSF  Hepatic metabolism to the inactive glucuronide is the major route of elimination. This metabolite and chloramphenicol itself are excreted in the urine. About 50% of chloramphenicol is bound to plasma proteins; such binding is reduced in cirrhotic patients and in neonates  Patients with cirrhosis or otherwise impaired hepatic function have decreased metabolic clearance, and dosage should be adjusted in these individuals