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Psi 2

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Psi 2

  1. 1. Protein Synthesis Inhibitors Claro M. Isidro M.D.
  2. 2. Protein Synthesis <ul><li>Stages of Protein Synthesis </li></ul><ul><li>1. Initiation - involves formation of an initiation complex that contains mRNA, both subunits of ribosomes and the first aminoacyl-tRNA (formyl-methionyl tRNA) </li></ul><ul><li>2. Elongation - includes synthesis of the first peptide bond to addition of the last amino acid. Also involved </li></ul><ul><ul><li>Peptide bond formation - polypeptide is transferred from peptidyl-tRNA in the P site to aminoacyl-tRNA in the A site </li></ul></ul><ul><ul><li>Translocation - moves ribosome one codon; places peptidyl-tRNA in the P site; deacylated tRNA leaves via the E site; A site is empty for next aa-tRNA </li></ul></ul>
  3. 3. Summary <ul><li>3. Termination – encompasses the release of the completed polypeptide chain and dissociation of the ribosome from the mRNA. </li></ul>
  4. 5. Protein Synthesis Inhibitors <ul><li>30 S INHIBITORS </li></ul><ul><li>A minoglycoside </li></ul><ul><li>T etracyclines </li></ul><ul><li>Buy AT 30 , CELLS at 50 </li></ul><ul><li>50 S INHIBITORS </li></ul><ul><li>C hloramphenicol </li></ul><ul><li>Macrolides ( E rythromycin) </li></ul><ul><li>C l indamycin </li></ul><ul><li>Oxazoladinones ( l inozelid) </li></ul><ul><li>S treptogramins </li></ul>
  5. 6. I. AMINOGLYCOSIDES <ul><li>Older Aminoglycosides: </li></ul><ul><li>Streptomycin </li></ul><ul><li>Kanamycin </li></ul><ul><li>Newer Aminoglycosides: </li></ul><ul><li>Gentamicin </li></ul><ul><li>Netilmicin </li></ul><ul><li>Tobramycin </li></ul><ul><li>Sisomicin </li></ul><ul><li>Neomycin </li></ul><ul><li>Paromomycin </li></ul><ul><li>Amikacin </li></ul>
  6. 7. I. AMINOGLYCOSIDES <ul><li>Antimicrobial Spectrum: </li></ul><ul><li>Gram (-) Aerobic Bacilli </li></ul><ul><li>Beta-lactamase producers: </li></ul><ul><li>Staph. aureus </li></ul><ul><li>N. gonorrhea </li></ul><ul><li>Mycobacteria </li></ul>
  7. 8. I. AMINOGLYCOSIDES <ul><li>Mechanism of Action: </li></ul><ul><li>interferes with initiation complex of peptide formation </li></ul><ul><li>induces misreading of mRNA causing incorporation of incorrect AA </li></ul><ul><li>causes breakup of polysomes into nonfunctional monosomes </li></ul><ul><li>Require oxygen uptake, therefore ineffective against anaerobes. </li></ul><ul><li>Bactericidal </li></ul>
  8. 9. I. AMINOGLYCOSIDES <ul><li>Microbial Resistance: </li></ul><ul><li>enzyme inactivation </li></ul><ul><li>Cell surface alteration </li></ul><ul><li>receptor protein alteration </li></ul><ul><li>oxygen requirement related </li></ul>
  9. 10. I. AMINOGLYCOSIDES <ul><li>Kinetics: </li></ul><ul><li>Very poorly absorbed from intact GIT, well absorbed thru IM, IV </li></ul><ul><li>They are highly polar compounds that do not enter the cells readilly, poorly penetrate the BBB </li></ul><ul><li>not significantly metabolized </li></ul><ul><li>primarily excreted unchanged through GF </li></ul>
  10. 11. I. AMINOGLYCOSIDES <ul><li>Clinical Uses: </li></ul><ul><li>severe gram (-) enteric bacteria especially when there is suspicion of sepsis </li></ul><ul><li>always used in combination with a beta-lactam antibiotic to extend coverage to include potential gram (+) pathogens </li></ul><ul><li>Penicillin aminoglycoside combinations also are used to achieve bactericidal activity in treatment of enterococcal endocarditis and to shorten duration of therapy for viridans streptococcal and staphylococcal endocarditis </li></ul><ul><li>Mycobacterial infections </li></ul>
  11. 12. I. AMINOGLYCOSIDES <ul><li>Toxicity: </li></ul><ul><li>Ototoxicity (esp. with loop diuretics) </li></ul><ul><ul><li>Auditory damage – Neomycin, Kanamycin and Amikacin </li></ul></ul><ul><ul><li>Vestibular damage- Streptomycin, Gentamicin </li></ul></ul><ul><li>Nephrotoxicity (esp. with vancomycin & amphotericin) </li></ul><ul><li>Neomycin, Tobramycin, Gentamicin - most nephrotoxic </li></ul>
  12. 13. STREPTOMYCIN <ul><li>ribosomal resistance to this agent develops readily, limiting its role as a single agent </li></ul><ul><li>Mainly used as 2 nd line agent for the treatment of tuberculosis given at 0.5-1 g/d , IM or IV. </li></ul><ul><li>usually given in drug combination to prevent emergence of resistance. </li></ul><ul><li>In plague, tularemia and sometimes brucellosis, 1 g/d (15 mg/kg/d for children) IM or IV + oral tetracycline is used </li></ul><ul><li>+ Penicillin; effective for enterococcal endocarditis and 2 week therapy of viridans streptococcal endocarditis. </li></ul><ul><li>can cause pain at the injection site, fever, skin rashes and other allergic reactions </li></ul><ul><li>most serious toxic effect is vestibular dysfunction </li></ul><ul><li>if given during pregnancy, can cause deafness in the newborn </li></ul>
  13. 14. GENTAMICIN <ul><li>in severe infections (sepsis and pneumonia) caused by gram (-) bacteria that are likely resistant to other drug, used in combination with a cephalosporin or a penicillin </li></ul><ul><li>given at 5-6 mg/kg/d IV in three equal doses </li></ul><ul><li>+ Penicillin G for bactericidal activity in endocarditis due to viridans streptococci or enterococci and in combination with Nafcillin in selected cases of staphylococcal endocarditis </li></ul>
  14. 15. Gentamicin <ul><li>Nei ther gentamicin nor any other aminoglycosides should be used for single agent therapy of pneumonia because penetration of infected lung tissue is poor and local condition of low pH and low oxygen contribute to poor activity </li></ul><ul><li>Serum concentrations and renal function should be monitored if administration for more than a few days or if renal function is changing </li></ul>
  15. 16. GENTAMICIN <ul><li>Gentamicin sulfate 0.1% - 0.3% cream, ointment – for the treatment of infected burns, wounds, or skin lesions and the prevention of intravenous catheter infections. </li></ul><ul><li>Topical gentamicin is partly inactivated by purulent exudates </li></ul><ul><li>Ten milligrams can be injected subconjunctivally for treatment of ocular infections </li></ul><ul><li>Nephrotoxicity is reversible and usually mild </li></ul><ul><li>Ototoxicity is Irreversible manifested as vestibular dysfunction </li></ul><ul><li>hypersensitivity reactions are uncommon </li></ul>
  16. 17. TOBRAMYCIN <ul><li>Antimicrobrial spectrum and pharmacokinetic properties is identical to gentamicin </li></ul><ul><li>Given at 5-6 mg/kg IM or IV into three equal amounts q 8 hours. </li></ul><ul><li>Blood levels should be monitored in renal insufficiency </li></ul><ul><li>Slightly more active against pseudomonas but not to E. faecium </li></ul><ul><li>Ototoxic and nephrotoxic </li></ul>
  17. 18. AMIKACIN <ul><li>semisynthetic derivative of kanamycin </li></ul><ul><li>resistant to many inactivating enzymes </li></ul><ul><li>Strains of multiple drug resistant tuberculosis, including Streptomycin resistant are usually susceptible </li></ul><ul><li>given at 7.5 -15mg/kg/d as a once-daily or 2-3x weekly </li></ul><ul><li>Serum concentrations should be monitored </li></ul><ul><li>Nephrotoxic and ototoxic (auditory portion of CN VIII) </li></ul>
  18. 19. NETILMICIN <ul><li>shares many characteristics with gentamicin and tobramycin </li></ul><ul><li>dosage and the routes of administration are the same </li></ul><ul><li>completely therapeutically interchangeable with gentamicin or tobramycin and has similar toxicities </li></ul>
  19. 20. KANAMYCIN & NEOMYCIN <ul><li>Paromomycin </li></ul><ul><li>Used for bowel preparation for elective surgery </li></ul><ul><li>Complete cross-resistance between kanamycin and neomycin </li></ul><ul><li>Not significantly absorbed from the GIT; excretion of any absorbed drug is mainly through GF into the urine </li></ul><ul><li>Too toxic for parenteral use, now limited to topical and oral use </li></ul><ul><li>Solutions 1-5 mg/ml- used applied on infected surfaces or injected into joints, pleural cavity, tissue spaces or abscess cavities where infection is present. ( 15 mg/kg/d) </li></ul><ul><li>Ointments (Neomycin-Polymyxin-Bacitracin combination); applied to infected skin lesions or in the nares for suppression of staphylococci </li></ul>
  20. 21. KANAMYCIN & NEOMYCIN <ul><li>In preparation for elective bowel surgery, 1 g of Neomycin given orally q 6-8 hours + 1 g of erythromycin base </li></ul><ul><li>Paromomycin, 1 g q 6 hours orally for 2 weeks is effective in intestinal amebiasis </li></ul><ul><li>Nephrotoxic and ototoxic ( Auditory dysfunction) </li></ul><ul><li>Sudden absorption of postoperatively instilled kanamycin from the peritoneal cavity (3-5 g) has resulted in curare-like neuromuscular blockade and respiratory arrest (Calcium gluconate and neostigmine can act as antidotes) </li></ul><ul><li>Prolonged application to skin and eyes-severe allergic reactions </li></ul>
  21. 22. SPECTINOMYCIN <ul><li>chemically related to the aminoglycosides </li></ul><ul><li>binds at the 30 S subunit (bacteriostatic) </li></ul><ul><li>dispensed as the dihydrochloride pentahydrate for IM injection </li></ul><ul><li>used solely as an alternative treatment for gonorrhea in patients who are allergic to penicillin or whose gonococci are resistant to other drugs </li></ul><ul><li>single dose of 2 g (40 mg/kg) </li></ul><ul><li>Can cause pain at the injection site , occasionally fever and nausea </li></ul><ul><li>Nephrotoxicity and anemia – rare </li></ul>
  22. 23. II.TETRACYCLINES : <ul><li>Short Acting: </li></ul><ul><li>Tetracyline, Oxytetracycline, Chlortetracycline </li></ul><ul><li>Intermediate Acting: Demeclocycline, Methacycline </li></ul><ul><li>Long Acting: </li></ul><ul><li>Doxycycline, Minocycline </li></ul>
  23. 24. II. TETRACYCLINES <ul><li>Antimicrobial Spectrum: </li></ul><ul><li>Rickettsia, V. cholera, M. pneumonia, Chlamydia, Shigella, H. pylori, P.tularensis, P.pseudomallei, Brucella, Psittacosis, Borrelia </li></ul><ul><li>Minocycline – carrier state of Meningococcal infections, N. asteroides, N. gonnorhea </li></ul>
  24. 25. II. TETRACYCLINES <ul><li>Mechanism of Action: </li></ul><ul><li>enter microorganisms in part by passive diffusion and in part by an energy-dependent process of active transport </li></ul><ul><li>binds to 30S subunit, blocking the binding of amino-acyl t-rna to the acceptor site and prevents the addition of amino acids to the growing peptide </li></ul><ul><li>Bacteriostatic </li></ul>
  25. 26. II. TETRACYCLINES <ul><li>Resistance: </li></ul><ul><li>decreased intracellular accumulation due to impaired influx or increased efflux by an active transport protein pump </li></ul><ul><li>ribosome protection due to production of proteins that interfere with tetracycline binding to the ribosome </li></ul><ul><li>enzymatic inactivation </li></ul>
  26. 27. II. TETRACYCLINES <ul><li>Kinetics </li></ul><ul><li>Distributed widely to tissue and body fluids except for CSF </li></ul><ul><li>Absorption occurs mainly in the upper small intestine and is impaired by food (except Doxycyline and Minocycline) </li></ul><ul><li>Must not be taken with dairy products or antacids </li></ul><ul><li>Cross placenta, excreted in milk </li></ul><ul><li>As result of chelation with Ca, they are bound to and damage growing bones and teeth </li></ul><ul><li>Carbamazepine, phenytoin, barbiturates, and chronic alcohol ingestion may shorten the half-life of doxycycline </li></ul><ul><li>Excreted mainly in bile and urine (Doxycycline fecally eliminated; can be used in renal failure) </li></ul>
  27. 28. II. TETRACYCLINES <ul><li>Clinical Uses: </li></ul><ul><li>DOC in infection with M. pneumoniae, chlamidiae,ricketsiae,and spirochetes. </li></ul><ul><li>No longer recommended for gonococcal disease due to resistance. Usually use in combination aminoglycosides </li></ul><ul><li>Borrelia burgdorfi (Lyme disease), Chlamydia, Ureaplasma, Acne, Tularemia, Cholera, Leptospirosis, Protozoal infections </li></ul><ul><li>Minocycline, 200 mg orally daily for 5 days – can eradicate the meningococcal carrier state </li></ul><ul><li>Demeclocycline – inhibits the action of ADH in the renal tubule and has been used in the treatment of inappropriate secretion of ADH or similar peptides by certain tumors </li></ul>
  28. 29. II. TETRACYCLINES <ul><li>Clinical Uses: </li></ul><ul><li>Tetracyclines – 250-500 mg 4x/day adults; 20-40 mg/kg/d-children above 8 y/o </li></ul><ul><li>Demeclocycline and Methacycline -> 600 mg daily </li></ul><ul><li>Doxycyline and Minocycline -> 100 mg 1-2x/d </li></ul><ul><li>Toxicity: </li></ul><ul><li>Renal toxicity, local tissue toxicity, photosensitization, GI distress, discolors teeth, inhibits bone growth in children, potentially teratogenic, hepatotoxicity, vestibular toxicity </li></ul>
  29. 30. THE 50 S INHIBITORS: <ul><li>CHLORAMPHENICOL </li></ul><ul><li>MACROLIDES </li></ul><ul><li>CLINDAMYCIN/LINCOMYCIN </li></ul><ul><li>STREPTOGRAMINS </li></ul><ul><li>OXAZOLADINONES </li></ul>
  30. 31. I. CHLORAMPHENICOL <ul><li>Bactericidal – H. influenzae, N. meningitides, B. fragilis </li></ul><ul><li>Bacteriostatic – S. epidermidis, S. aureus, , M. pneumonia, L. monocytogenes, C.diphtheria, L. multocida, Salmonella sp., Shigella sp., E. coli, Rickettsia, Anaerobes </li></ul>
  31. 32. I. CHLORAMPHENICOL <ul><li>MECHANISM OF ACTION: </li></ul><ul><li>Bind to the 50 S subunit of microbial ribosomes and blocks the functional attachment of amino-acyl-tRNA to the acceptor site </li></ul><ul><li>inhibits peptidyl transferase step </li></ul>
  32. 33. I. CHLORAMPHENICOL <ul><li>SPECTRUM: </li></ul><ul><li>broad spectrum antibiotic </li></ul><ul><li>more effective than Tetracyclines against Typhoid Fever and other Salmonella infections </li></ul>
  33. 34. I. CHLORAMPHENICOL <ul><li>KINETICS: </li></ul><ul><li>well absorbed after oral administration; usual dosage is 50-100 mg/kg/d </li></ul><ul><li>Chloramphenicol succinate used for parenteral administration is highly water soluble </li></ul><ul><li>Well distributed to all tissues & body fluids, including the CSF, ocular and joint fluids </li></ul><ul><li>rapidly excreted in urine, 10% as chloramphenicol; 90% as glucuronide conjugate; small amount of active drug is excreted into bile or feces </li></ul><ul><li>systemic dosage need not be altered in renal insufficiency but must be reduced markedly in hepatic failure </li></ul><ul><li>Newborns less than a week old and premature infants also clear Chloramphenicol less well, dosage should be reduced at 25 mg/kg/d. </li></ul>
  34. 35. I. CHLORAMPHENICOL <ul><li>CLINICAL USES: </li></ul><ul><li>Meningitis, Rickettsia, Salmonella and anaerobic infections; </li></ul><ul><li>ineffective against chlamydial infections </li></ul><ul><li>occasionally used topically in the treatment of eye infections for its well penetration to ocular tissues and the aqueous humor </li></ul><ul><li>ADVERSE EFFECTS: </li></ul><ul><li>GIT, oral or vaginal candidiasis, irreversible aplastic anemia, reversible bone marrow depression, Gray Baby Syndrome </li></ul>
  35. 36. II. MACROLIDES: <ul><li>Old Generation: </li></ul><ul><li>Erythromycin, Oleandomycin, Troleandomycin, Spiramycin, Josamycin </li></ul><ul><li>New Generation: </li></ul><ul><li>Rosaramycin, Roxithromycin, Clarithromycin, Azithromycin, Dirithromycin </li></ul>
  36. 37. II. MACROLIDES <ul><li>MECHANISM OF ACTION: </li></ul><ul><li>binds to the P site of the 50 S bacterial ribosomal subunit. </li></ul><ul><li>Aminoacyl translocation and formation of initiation complex are blocked </li></ul><ul><li>Inhibitory or bactericidal </li></ul>
  37. 38. II. MACROLIDES <ul><li>RESISTANCE: </li></ul><ul><li>reduced permeability of the cell membrane or active efflux </li></ul><ul><li>production (by Enterobacteriaceae) of esterases that hydrolyze macrolides </li></ul><ul><li>modification of the ribosomal binding site by chromosomal mutation </li></ul>
  38. 39. II. MACROLIDES <ul><li>SPECTRUM: </li></ul><ul><li>Erythromycin has a narrow Gram (+) spectrum similar to Pen. G. </li></ul><ul><li>DOC in corynebacterial infection (diptheria and corynebacterial sepsis) </li></ul><ul><li>Also active against Chlamydia and Legionella organisms </li></ul>
  39. 40. Erythromycin <ul><li>prototype </li></ul><ul><li>distributed widely to the body fluids except CSF </li></ul><ul><li>Base form easily destroyed by stomach acid & must be administered with enteric coating </li></ul><ul><li>food interferes with absorption </li></ul><ul><li>serum half life is app. 1.5 h normally and 5 hours in patients with anuria </li></ul><ul><li>is not removed by dialysis </li></ul><ul><li>metabolized in the liver excreted in the bile & feces </li></ul><ul><li>traverses the placenta and reaches the fetus </li></ul><ul><li>COMMERCIAL PREPARATIONS: </li></ul><ul><li>Oral-stearate, ethyl succinate, estolate salts: 250-500 mg q 6 h </li></ul><ul><li>Parenteral- lactobionate, gluceptate : 0.5-0.1. g q 6 hours </li></ul>
  40. 41. Erythromycin <ul><li>ADVERSE EFFECTS: </li></ul><ul><li>GIT dysfunction, intrahepatic cholestatic jaundice (particularly with estolate prep) </li></ul><ul><li>erythromycin metabolites can inhibit cytochrome p450 enzymes & thus increase the serum concentrations of theophylline, oral anticoagulants, cyclosporine, methylprednisolone and digoxin by increasing its bioavailability </li></ul>
  41. 42. Clarithromycin <ul><li>Derive from erythromycin by addition of methyl group </li></ul><ul><li>more active against Gram (+) pathogens, Legionella and Chlamydia than Erythromycin </li></ul><ul><li>lower frequency of GIT effects, less frequent dosing </li></ul><ul><li>half life of 6 hours </li></ul><ul><li>given at 250-500 mg twice daily </li></ul>
  42. 43. Azithromycin <ul><li>Active against M. avium and T.gondii </li></ul><ul><li>Less active than erythromycin and chlarithromycin against staph. and strep. </li></ul><ul><li>More active against H. influenzae and chlamydia </li></ul><ul><li>Penetrates into most tissues (except CSF) and phagocytic cells extremely well </li></ul><ul><li>maintains high concentrations for prolonged periods into a number of tissues (lungs, tonsils, cervix) </li></ul><ul><li>tissue half life – 2-4 days </li></ul><ul><li>long half-life allows once daily oral administration and shortening of treatment in many cases ( a single 1 g dose of azithromycin is as effective as a 7 day course of doxycycline for chlamydial cervicitis and urethritis ) </li></ul>
  43. 44. Azithromycin <ul><li>Community acquired pneumonia – 500 mg loading dose, followed by a 250 mg single daily dose for the next 4 days </li></ul><ul><li>should be administered 1 hour before or 2 hours after meals; aluminum and magnesium delay absorption and reduce peak serum concentrations </li></ul><ul><li>does not inactivate cytochrome p450 enzymes and free of the drug interactions that occur with erythromycin and clarithromycin </li></ul>
  44. 45. III. CLINDAMYCIN / LINCOMYCIN <ul><li>MECHANISM OF ACTION: </li></ul><ul><li>attach to 50 S ribosomal subunit, inhibits protein synthesis by interfering with the formation of initiation complexes and translocation reaction </li></ul><ul><li>SPECTRUM: </li></ul><ul><li>Narrow Gram (+) spectrum, excellent activity against anaerobic bacteria; strep, pneumococci, staphylococci </li></ul>
  45. 46. III. CLINDAMYCIN / LINCOMYCIN <ul><li>RESISTANCE: </li></ul><ul><li>mutation of the ribosomal receptor site </li></ul><ul><li>modification of the receptor by a constitutively expressed methylase </li></ul><ul><li>enzymatic inactivation </li></ul>
  46. 47. III. CLINDAMYCIN / LINCOMYCIN <ul><li>Clindamycin is more clinically used than Lincomycin </li></ul><ul><li>Penetrates well into most tissue except brain and CSF </li></ul><ul><li>given at 150-300 mg q 6 hrs adults ;10-20 mg/kg/d for children </li></ul><ul><li>well bone penetration </li></ul><ul><li>Metabolized in the liver, excreted in the bile and urine </li></ul><ul><li>half life is 2.5 hours normally and 6 hours in patients with anuria </li></ul><ul><li>more toxic than erythromycin </li></ul>
  47. 48. CLINDAMYCIN <ul><li>Clinical uses: </li></ul><ul><li>prophylaxis of endocarditis in patients with valvular heart disease for dental procedures </li></ul><ul><li>most important indication is the treatment of severe anaerobic infection caused by bacteroides and other anaerobes that often participate in mixed infections </li></ul><ul><li>+ aminoglycoside or cephalosporin- used to treat penetrating wounds of the abdomen & gut, septic abortion, pelvic abscesses, aspiration pneumonia </li></ul>
  48. 49. CLINDAMYCIN <ul><li>+ primaquine – effective alternative to trimethoprim sulfamethoxazole for moderate to moderately severe Pneumocystis carinii pneumonia in AIDS patients </li></ul><ul><li>+ pyrimethamine – in AIDS related toxoplasmosis of the brain. </li></ul><ul><li>ADVERSE EFFECTS: </li></ul><ul><li>Diarrhea, nausea , skin rashes, impaired liver function and neutropenia </li></ul><ul><li>Antibiotic associated colitis caused by toxigenic C. difficile. </li></ul>
  49. 50. STREPTOGRAMINS <ul><li>Quinupristin-Dalfopristin (Synercid) </li></ul><ul><li>action is similar to macrolides </li></ul><ul><li>bactericidal for staph and most organisms except Enterococcus faecium </li></ul><ul><li>prolonged postantibiotic effect up to 10 h for Staph. aureus </li></ul><ul><li>administered IV at 7.5 mg/kg q 8 -12 h </li></ul><ul><li>eliminated through fecal route, < 20% urine </li></ul><ul><li>Patients with hepatic insufficiency may not tolerate the drug at usual doses </li></ul><ul><li>inhibits CYP 3A4 P450, which metabolizes warfarin, diazepam, astemizole, terfenadine, cisapride, nonnucleoside reverse transcriptase inhibitors and cyclosporine. </li></ul>
  50. 51. STREPTOGRAMINS <ul><li>Clinical Uses: </li></ul><ul><li>infections caused by Vancomycin resistant strains of E faecium but not E. faecalis, </li></ul><ul><li>bacteremia or respiratory tract infections caused by methicillin-resistant staphylococci and penicillin susceptible and resistant strains of S. pneumonia </li></ul><ul><li>Toxicities: </li></ul><ul><li>infusion related events like pain at the injection site, arthralgia, myalgia </li></ul>
  51. 52. OXAZOLADINONES: Linezolid (Zyvox) <ul><li>inhibits protein synthesis by preventing formation of the ribosome complex that initiated protein synthesis. </li></ul><ul><li>Its unique binding site located on the 23 S ribosomal RNA of the 50 S subunit, results in no cross resistance with other drug classes </li></ul><ul><li>Has high oral bioavailability, half life of 4-6 h </li></ul><ul><li>Uses : staph, strep, enterococci, G(+) anaerobic cocci, G (+) rods, Corynebacterium, and L. monocytogenes </li></ul><ul><li>treatment of infections caused by vancomycin resistant E. faecium and other infections caused by multiple drug resistant organisms. </li></ul>
  52. 53. METABOLIC INHIBITORS Claro M. Isidro M.D.
  53. 54. SULFONAMIDES <ul><li>METABOLIC INHIBITORS </li></ul><ul><li>Sulfonamides </li></ul><ul><li>structural analogs of PABA </li></ul><ul><li>competitively inhibit dihydropteroate synthase (catalyzed the synthesis dihydropteroic acid) </li></ul><ul><li>inhibits growth by reversibly blocking folic acid synthesis </li></ul><ul><li>bacteriostatic </li></ul>
  54. 56. SULFONAMIDES <ul><li>Spectrum of activity: </li></ul><ul><li>Inhibit the growth both Gm (+) and Gm (-) bacteria, Nocardia, Chlamydia trachomatis & some protozoa </li></ul><ul><li>Enteric bacteria such as E.coli,klebsiella, salmonella,shigella, and enterobacter are also inhibited </li></ul><ul><li>Rickettsia – not inhibited but growth stimulated by sulfas </li></ul>
  55. 57. SULFONAMIDES <ul><li>RESISTANCE </li></ul><ul><li>occur as a result of mutations that: </li></ul><ul><ul><li>cause overproduction of PABA </li></ul></ul><ul><ul><li>cause production of a folic acid synthesizing enzyme that has a low affinity for sulfonamides </li></ul></ul><ul><ul><li>cause a loss of permeability to sulfonamides </li></ul></ul>
  56. 58. SULFONAMINDES <ul><li>Pharmacokinetics: three major groups </li></ul><ul><li>oral, absorbable </li></ul><ul><li>a. short-acting: sulfacytine, sulfisoxazole, sulfamethizole </li></ul><ul><li>b. medium- acting: sulfadiazine, sulfamethoxazole, sulfapyridine </li></ul><ul><li>c. long- acting: sulfadoxine </li></ul><ul><li>oral, nonabsorbable </li></ul><ul><li>a. Sulfasalazine </li></ul><ul><li>b. Olsalazine </li></ul>
  57. 59. SULFONAMIDES <ul><li>topical </li></ul><ul><li>a.Sodium sulfacetamide ophthalmic sol’n or ointment – for bacterial conjunctivitis </li></ul><ul><li>b. Mafenide acetate- prevent bacterial colonization and infection of burn wounds </li></ul><ul><li>c. Silver sulfadiazine –prevent of infection in burn wounds </li></ul>
  58. 60. SULFONAMIDES <ul><li>Pharmacokinetics </li></ul><ul><li>Well absorbed from the GIT </li></ul><ul><li>Widely distributed in the body including the CNS, placenta & fetus </li></ul><ul><li>Highly bound to albumin </li></ul><ul><li>Acetylated or glucorinated in the liver </li></ul><ul><li>Excreted into the urine – mainly by glomerular filtration </li></ul>
  59. 61. SULFONAMIDE <ul><li>SPECTRUM: gram (+) & gram (-) </li></ul><ul><li>Simple urinary tract infection </li></ul><ul><li>Ocular infection </li></ul><ul><li>Burn infections </li></ul><ul><li>Ulcerative colitis </li></ul><ul><li>With pyrimethamine: Toxoplasmosis </li></ul><ul><li>Malaria </li></ul>
  60. 62. SULFONAMIDES <ul><li>Adverse Reaction </li></ul><ul><li>Hypersensitivity Reaction </li></ul><ul><li>Photosensitivity </li></ul><ul><li>Nausea & vomiting </li></ul><ul><li>Hemolytic anemia </li></ul><ul><li>Crystalluria & nephrotoxicity ( tx alkalinize the urine by NaHCO 3 </li></ul><ul><li>Kernicterus in the newborn </li></ul><ul><li>CI: Pregnancy & newborn </li></ul><ul><li>DI: Compete with wafarin, tolbutamide, methotrexate for PPB </li></ul>
  61. 63. TRIMETOPRIM SULFAMETHOXAZOLE (CO-TRIMOXAZOLE) <ul><li>COMBINATION CAUSES: </li></ul><ul><li>1. INCREASE POTENCY </li></ul><ul><li>2. INCREASE SPECTRUM </li></ul><ul><li>3. DECREASE INCIDENCE OF RESISTANCE </li></ul><ul><li>MOA: blocks the sequential steps in the obligate enzymatic reaction in bacteria preventing formation of nucleotide </li></ul>
  62. 64. CO-TRIMOXAZOLE <ul><li>Pharmacokinetcs </li></ul><ul><li>Trimetoprim: more lipid soluble, greater Vd </li></ul><ul><li>Given in 1: 5 ratio </li></ul><ul><li>CLINICAL USES </li></ul><ul><li>SPECTRUM: broad gm + & gm – </li></ul><ul><li>UTI, pneumonia, gonorrhea & prostatitis, Acute chronic bronchitis, acute otitis media, chancroid, shigellosis, typhoid fever, nocardiosis </li></ul>
  63. 65. CO-TRIMOXAZOLE <ul><li>HYPERSENSITIVITY REACTIONS </li></ul><ul><li>PHOTOSENSITIVITY </li></ul><ul><li>NAUSEA & VOMITING </li></ul><ul><li>HEMOLYTIC ANEMIA </li></ul><ul><li>CRYSTALLURIA & NEPHROTOXCITY </li></ul><ul><li>KERNICTERUS </li></ul><ul><li>CI: PREGNANCY & NEWBORN </li></ul><ul><li>DI: COMPETE WITH WARFARIN, METHOTREXATE FOR PPB </li></ul>
  64. 66. <ul><li>Other drug combinations </li></ul><ul><li>Sulfadiazine + pyrimethamine </li></ul><ul><li>for leishmaniasis & toxoplasmosis </li></ul><ul><li>2. Sulfadoxime + pyrimethamine </li></ul><ul><li>for Falciparum malaria </li></ul>
  65. 67. NUCLEIC ACID SYNTHESIS INHIBITORS <ul><li>First Generation: Nalidixic acid </li></ul><ul><li>Second Generation: Ofloxacin, Ciprofloxacin, Norfloxacin, Levofloxacin </li></ul><ul><li>Third Generation: Gatifloxin, Sparfloxacin Clinafloxacin, </li></ul><ul><li>Fourth Generation: Trovafloxacin, Moxifloxacin </li></ul>
  66. 68. Fluoroquinolones <ul><li>Bactericidal </li></ul><ul><li>Inhibits DNA Gyrase or Topoisomerase II - Block the relaxation of supercoiled DNA that is catalyzed by DNA gyrase </li></ul><ul><li>Inhibits Topoisomerase IV – interferes with the separation of replicated chromosomal DNA during cell division </li></ul>
  67. 69. Fluoroquinolones <ul><li>Resistance </li></ul><ul><li>Modification of DNA Gyrase </li></ul><ul><li>Decreased accumulation in the bacterial cell due to : </li></ul><ul><ul><li>reduction of the porin proteins in the outer membrane </li></ul></ul><ul><ul><li>energy dependent efflux system of the inner membrane </li></ul></ul>
  68. 70. Fluoroquinolones <ul><li>Clinical Uses </li></ul><ul><li>SPECTRUM: broad ; aerobic gm (+) & gm (-) but not anaerobes </li></ul><ul><li>UTI </li></ul><ul><li>Sexually transmitted diseases : Gonorrhea, Chlamydia, chacroid, Prostatitis </li></ul><ul><li>Respiratory infection due to H. influenza, M. catarrhalis, Strep pneumoniae, M. pneumoniae </li></ul><ul><li>Nosocomial infection (P. aeroginosa) </li></ul><ul><li>GIT infections due to : E.coli, Shigella, & Salmonella </li></ul><ul><li>Chronic bone infection due to Pseudomonas & Staph. aereus </li></ul><ul><li>Diabetic foot infections </li></ul>
  69. 71. CIPROFLOXACIN <ul><li>Most widely used </li></ul><ul><li>DOC for anthrax </li></ul><ul><li>Most potent for P. aeroginosa </li></ul><ul><li>Synergistic with beta lactams </li></ul><ul><li>M. tuberculosis </li></ul><ul><li>NORfLOXACIN </li></ul><ul><li>Not effective in systemic infection </li></ul>
  70. 72. LEVOFLOXACIN <ul><li>Prostatitis ,E. coli </li></ul><ul><li>Sexually transmitted diseases, gonorrhea </li></ul><ul><li>Skin infections </li></ul><ul><li>S. pneumoniae </li></ul><ul><li>TROVA & MOXIFLOXACIN </li></ul><ul><ul><li>Anaerobes, P. AEROGINOSA </li></ul></ul><ul><ul><ul><li>GATIFLOXACIN </li></ul></ul></ul><ul><ul><li>Resp infection , S. pneuomoniae </li></ul></ul>
  71. 73. Fluoroquinolones <ul><li>Side Effects </li></ul><ul><li>Nausea & diarrhea </li></ul><ul><li>Headache, dizziness, light headedness </li></ul><ul><li>Arthralgia & joint swelling </li></ul><ul><li>Rashes & photophobia </li></ul>
  72. 74. Fluoroquinolones <ul><li>CI: PREGNANT WOMEN, NEONATES </li></ul><ul><li>ARRYTHMIAS: SPARFLOXACIN & </li></ul><ul><li>MOXIFLOXACIN: prolong QT intervals </li></ul><ul><li>DI: ↓ ABSORPTION WITH ANTACID , FeSo4 </li></ul><ul><li>Cimetidine interferes elimination </li></ul><ul><li>Ciprofloxacin & ofloxacin: ↑ theophylline levels </li></ul>
  73. 76. <ul><li>1-3. Three stages of protein synthesis </li></ul><ul><li>4. Drugs that inhibit 30S subunit </li></ul><ul><li>5. DOC for anthrax </li></ul><ul><li>6 & 7. Drugs that inhibit 50S subunit </li></ul><ul><li>8. Enzyme inhibited by sulfonamide </li></ul><ul><li>9. Enzyme inhibited by flouroquinolone </li></ul><ul><li>10. DOC for anaerobic infection </li></ul>

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