Lec 26. Chloramphenicol, Clindamycin, etc, Dr. Thomas Panavelil- FS PDF

MISCELLANEOUS PROTEIN SYNTHESIS INHIBITORS Thomas A. Panavelil, Ph.D., M.B.A. Spectinomycin Chloramphenicol Clindamycin Linezolid & Tedizolid Dalfopristin/Quinupristin Lefamulin (a pleuromutilin) Bacterial protein synthesis & drug targets ...

MISCELLANEOUS PROTEIN SYNTHESIS INHIBITORS Thomas A. Panavelil, Ph.D., M.B.A. Spectinomycin Chloramphenicol Clindamycin Linezolid & Tedizolid Dalfopristin/Quinupristin Lefamulin (a pleuromutilin) Bacterial protein synthesis & drug targets  SPECTINOMYCIN Spectinomycin is a related aminocyclitol antibiotic that lacks amino sugars and glycosidic bonds. In vitro it is active against gram-positive and gram-negative organisms. Streptomyces spectabilis IS bacteriostatic. Spectinomycin binds to the bacterial 30S ribosomal subunit and interferes with the elongation process. Spectinomycin is used almost solely as an alternative treatment for gonorrhea in patients who are allergic to penicillin or when gonococci are resistant to other agents. Used intramuscularly as a single dose of 2 gms (40mg/kg body weight). There is pain at the site of injection and it may cause fever, nausea, nephrotoxicity and anemia rarely. Chloramphenicol  CHLORAMPHENICOL Mechanism: Chloramphenicol binds to 50S ribosomal subunit and inhibits transpeptidation (catalyzed by peptidyl transferase) by blocking the binding of charged tRNA to the acceptor site on the ribosome-mRNA complex. Thus peptide at the donor site cannot be transferred to its amino acid acceptor. Pharmacokinetics: It is effective orally and parenterally. It is distributed throughout all tissues, and it readily crosses placental and blood-barriers. Concentration of chloramphenicol in brain tissue may become equal to that in serum. Most of the drug is inactivated either by conjugation with glucuronic acid (in liver) or by reduction to inactive aryl amines. Antimicrobial activity: Broad spectrum antibiotic with bacteriostatic activity. It is active against aerobic and anaerobic gram-positive and gram- negative organisms including Rickettsia. It is an alternative agent to beta-lactam antibiotic for treatment of bacterial meningitis caused by beta-lactam resistant strains of pneumococci or meningococci, or in patients with major hypersensitivity to beta lactams.  Chloramphenicol………… Resistance: Resistance to the drug is plasmid mediated through the formation of acetyltransferases that inactivate the drug. Clinical Uses: Chloramphenicol is a toxic drug. Because of its toxicity, it is rarely used as a systemic drug. It is used as a back-up drug for severe salmonella infections and in pneumococcal and meningococcal meningitis in beta-lactam-sensitive persons. It is also used in Rickettsial (gm-N, pleomorphic rod or cocci, nonmotile) diseases. It is also used as a topical antimicrobial agent. Toxicity: GI disturbances, Inhibition of red cell maturation (bone marrow disturbance) and very rarely aplastic anemia. Gray baby syndrome (vomiting, flaccidity, gray color shock and collapse) because neonates lack hepatic glucuronosyltransferase, the enzyme required for the elimination of the drug (therefore used with caution). Cyanosis and cardiovascular collapse can happen upon accumulation of the drug. Drug interactions: Chloramphenicol inhibits the metabolism of several drugs including phenytoin and warfarin. Clindamycin CLINDAMYCIN (Cleocin, Evoclin) Mechanism: As a lincosamide, Clindamycin is an inhibitor of protein synthesis. By binding to 50S ribosomal subunit it prevents chain elongation. Clindamycin is not chemically related to macrolides, even though mechanism of action is similar. Resistance: Plasmid mediated inactivating enzymes and methylation of binding of site on the 50S ribosomal subunit. Cross- resistance between lincosamide and macrolides are common. Adverse: GI irritation (severe diarrhea). skin rashes, neutropenia, hepatic dysfunction, superinfection such as C. difficile pseudomembranous colitis(overgrowth of C. difficile). May prolong the effects of neuromuscular blocking agents.  Clindamycin……… Clinical uses: Clindamycin is effective against gram-positive aerobes, and both gram-positive and gram-negative ANAEROBES. Its general use is restricted to the treatment of infections caused by susceptible strains of streptococci, staphylococci, pneumococci, or anaerobes such as bacteroides that are insensitive to less toxic antimicrobials such as penicillins. Clindamycin is indicated in refractory bone infections. The main use of clindamycin is in the treatment of severe infections due to anaerobes such as Bacteroides. Clindamycin is used as a drug against gram-positive cocci, also is recommended for prophylaxis of endocarditis in patients with valvular disease who are penicillin allergic. The drug has good activity against P. jirovecii and T. gondii. Additional comments: Clindamycin is recommended (American Dental Association) as an alternative antibiotic (after amoxicillin) for prophylactic coverage of patients at risk of developing bacterial endocarditis or endoarteritis as a result of bacteremia caused by dental and oral procedures. Linezolid (Zyvox) & Tedizolid (Sivextro) Mechanism: Binds to 23S ribosomal RNA on 50S ribosome and prevents the formation of 70S complex (a unique action). Linezoild belongs to the class oxazolidinones. It is available for parenteral, and oral administration. Distributes to all well-perfused tissues. Metabolized by oxidation. Does not induce CYP. Excretion is mainly non-renal. It is highly active against aerobic gram-positive organisms. Enterococcus faecium (used in concurrent bacteremia by VRE), Staph. aureus (MRSA), Strep. agalactiae (Group B streptococci, colonizes the genital tract of women and can cause neonatal meningitis and sepsis), Strep. pneumoniae (nosocomial) and Strep pyogenes. Linezolid is used to treat serious infections, such as pneumonia, skin infections, and infections that are resistant to other antibiotics. It is bacteriostatic against Enterococci and Staphylococci but is bactericidal against Streptococci. Adverse: Thrombocytopenia (3%), serotonin syndrome and bone marrow suppression are rare serious adverse effects. Diarrhea, rashes, vomiting, headache etc. are other adverse effects Tedizolid: For complicated skin and skin-structure infections (cSSSIs)  Quinupristin-Dalfopristin (Synercid) Belongs to the class Streptogramins. Quinupristin is a streptogramin A and Dalfopristin is a streptogramin B (the ratio is 3:7). It’s mechanism similar to macrolides. Dalfopristin and quinuprisin bind to 50s ribosome and prevents transfer and elongation. Both agents give additive protein synthesis inhibition. Given intravenously for vancomycin resistant enterococcus faecium, MSSA (methicillin-susceptible) or MRSA, VRSA and Strep. Pyogenes infections. Synercid treats soft tissues infections, pneumonia and bacteremia caused by susceptible organisms. It has no activity against E. faecalis.  quinupristin-dalfopristin……… Synercid is metabolized by non-enzymatic reactions, but the drug inhibits CYP3A4. The drug is bactericidal to Staph. aureus. Quinuprisitin can develop resistance via methylation. This action may be due to constitutive methylases, not by methylase induction? 90% susceptibility to VRE faecium. PAE (post antibiotic effect) is observed with Staph. aureus. Adverse effects include abdominal pain, acute respiratory distress syndrome (ARDS) and many other effects. Myalgia and hepatic transaminase activity are also reported.  Lefamulin (Xenleta) Lefamulin is a new agent in the pleuromutilin class MECHANISM OF ACTION: Lefamulin works by binding the 50S ribosome, Mechanism is unique in that it causes the binding pocket to close around the drug molecule, preventing bacterial transfer RNA from binding appropriately. ANTIBACTERIAL ACTIVITY: Lower respiratory tract pathogens such as Streptococcus pneumoniae, Hemophilus influenzae, and atypical pathogens such as Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydophila pneumoniae are susceptible. It also has in vitro activity against most aerobic gram-positive organisms, including S pyogenes, Staphylococcus aureus, and Enterococcus faecium. Lefamulin lacks activity against Enterococcus faecalis, Pseudomonas aeruginosaand the Enterobacteriaceae group of gram-negative organisms. Approval: for CAP, available oral & i.v.