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Chapter 42 Tetracyclines and Chloramphenicol

Chapter 42 Tetracyclines and Chloramphenicol. Tetracyclines. Natural: Tetracycline, oxytetracycline, chlortetracycline Semi-synthesized Doxycycline and minocycline. Tetracyclines. Antimicrobial activity Broad-spectrum bacteriostatic antibiotics

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Chapter 42 Tetracyclines and Chloramphenicol

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  1. Chapter 42 Tetracyclines and Chloramphenicol

  2. Tetracyclines • Natural: Tetracycline, oxytetracycline, chlortetracycline • Semi-synthesized Doxycycline and minocycline

  3. Tetracyclines • Antimicrobial activity • Broad-spectrum bacteriostatic antibiotics • Many gram-positive and gram-negative bacteria including anaerobes • Rickettsiae, chlamydiae and mycoplasm • Some protozoa: amebas

  4. Tetracyclines • Mechanism of action Tetracyclines bind reversibly to the 30s subunit of bacterial ribosome and block the binding of aminoactyl-tRNA to the acceptor site, prevent the elongation of peptide.

  5. Tetracyclines • Resistance • Production of an efflux pump • Ribosome protection due to production of proteins that interfere with tetracyclines binding to the ribosome • Production of enzyme

  6. Tetracycline • Pharmacokinetics • Absorption: affected by food ,divalent cations（Ca2+, Mg2+ , Fe2+）, dairy products and antiacid • Distribution: distribute widely to tissues and body fluids, bind to and damage growing bone and teeth as a result of chelation with calcium • Cross plancental barrier and excrete in milk

  7. Tetracyclines • Clinical uses • Rickettsiae infections : first choice • Chlamydiae pneumoniae • Mycoplasma infection • Relapsing fever: the most effective • Various gram-positive and negative infections • Gastric ulcer and duodenal ulcer caused by Helicobacter pylori in combination regimens

  8. Tetracycline • Adverse reactions • Gastrointestinal adverse effects • Superinfection • Pseudomembranous enterocolitis caused by clostridium difficile • Candida albicans infection • Effects on bony structure and teeth • Teeth: fluorescence, discoloration and enamel dysplasia • Bone: deformity or growth inhibition • Liver and kidney toxicity, photosensitization

  9. Synthesized tetracyclines • Doxycycline and minocycline • Almost completely absorbed • Long-acting: t 1/2 >14h • Higher activity than tetracycline • Effective against tetracycline-resistant bacteria • Low toxicity • Minocycline: the strongest activity/ vestibular disturbance

  10. Chloramphenicol

  11. Antimicrobial activity • Broad-spectrum bacteriostatic antibiotics • Both gram-positive and gram-negative aerobic and anaerobic organisms • Rickettsiae, spirochetes, mycoplasm

  12. Mechanism of action Chloramphenicol is a inhibitor of microbial protein synthesis. It binds reversibly to the 50s subunit of the ribosome and inhibits the peptidyl transferase step of protein synthesis

  13. Pharmacokinetics • Absorption : po • High concentration in CSF • Metabolized in liver

  14. Clinical uses • Bacterial menigitis caused by penicillin-resistant bacteria or penicillin-allergic patients • Typhoid and paratyphoid fever :first choice • Serious rickettsial infections • Topical use for treatment of eye infections

  15. Adverse reactions • Bone marrow disturbances • Reversible suppression of RBC production • Ireversible aplastic anemia • Graybaby syndrome • dose >50mg/kg/d • Gastrointestinal reactions

  16. Chapter 43 Synthetic organic antimicrobials

  17. Synthetic organic antimicrobials • Quinolones • Sulfonamides • Trimethoprim（TMP） • Nitrofurans • Metronidazole

  18. Quinolones • Brief introduction • Antibacterial activity • Mechanism of action • Clinical uses • Adverse reactions

  19. Brief introduction of quinolones • Four generations • First generation:1962 Lesher nalidixic acid • Second generation: 1973 pipemidic acid • Third generation: 1980’s fluoroquinolones • Fourth generation: late 1990’s moxifloxacin（莫西沙星）, gatifloxacin(加替沙星)

  20. Nalidixic acid—first generation • Narrow antibacterial spectrum:G- • Poorly absorbed • High adverse reactions

  21. Pipemidic acid--second generation • Higher activity than nalidixic acid • High concentration in urine • Less toxicity than nalidixic acid • Mainly used in gastrointestinal and urinary tract infection

  22. Fluoroquinolones—third generation • Norfloxacin —— 诺氟沙星 • Ciprofloxacin——环丙沙星 • Ofloxacin ——氧氟沙星 • Levoofloxacin——左氧氟沙星 • Lomefloxacin ——洛美沙星 • Fleroxacin ——氟罗沙星 • Sparfloxacin ——司帕沙星

  23. Fluoroquinolones • Antibacterial activity： broad spectrum • Excellent activity against gram-negative aerobic bacteria include enterobacteriaceae, neisseria, pseudomonas, haemophilus（嗜血杆菌属）and campylobacter（弯曲杆菌属）etc • Good activity against gram-positive aerobic bacteria : eg pneumoniae and staphylococci • Mycoplasmas, chlamydiae, mycobaterium tuberculosis, legionella and anaerobes

  24. Quinolones • Mechanism of action • To G-: DNA gyrase A2B2 • To G+: Topo Ⅳ C2E2 • Resistance • Mutation of target : gyrA or parC • Lack of OmpF on membrane • Active efflux pump

  25. Fluoroquinolones • Pharmacokinetics • Absorbed rapidly and completely • Widely distributed • Long T ½ • Low adverse reaction • No cross-resistance with other drugs

  26. Fluoroquinolones • Clinical uses • Urinary and genital tract infections • Respiratory tract infection: Legionella , chlamydia and mycoplasma pneumonia • Bacterial diarrhea caused by shigella, salmonella or campylobacter • Infections of soft-tissues, bones, joint • Tuberculosis : Ofloxacin, Sparfloxacin

  27. Fluoroquinolones • Adverse reactions • Gastrointestinal reaction: nausea, vomiting and diarrhea • CNS: headache, dizziness, insomnia and anxiety, seizure • Allergic effect: skin rash, photosensitivity • Damage growing cartilage and cause arthropathy

  28. Contradications • Pregnancy • Children • CNS disorder • History of epilepsy • Allergic

  29. Commonly used Quinolones

  30. Nalidixic acid and pipemidic acid • Used only in urinary tract infection • Norfloxacin • The least active in fluoroquinolones, F low • No effects on mycoplasmas, chlamydiae, mycobaterium tuberculosis, legionella • Urinary tract and intestinal tract infections • Ciprofloxacin(悉复欢) • The most active agent in fluoroquinolones against gram-negatives, particularly P. aeruginosa in vitro • No effects on anaerobes

  31. Ofloxacin(泰利必妥） • Improved quality in pharmacokinetics F 89% • Effective on mycobateria, chlamydiae and some anaerobes • Effective on resistant bacteria • Second line agent for tuberculosis • Levo-ofloxacin（可乐必妥,来立信） • F 100% • Superior activity against gram-positive organisms • Effective on mycoplasma, legionella, chlamydia and anaerobes • Lowest toxicity among fluoroquinolones

  32. Lomefloxacin: • F 98% t ½= 7h • To G+ and G-: Similar to ofloxacin • To anaerobes: < ofloxacin • Photosensitivity C8-F • Fleroxacin • F 100%, t ½>10h • Higher activity than ciprofloxacin and ofloxacin (in vivo)

  33. Sparfloxacin • Long-acting t ½>16h • Improved activity against G+ bacteria, anaerobes, mycobateria, mycoplasmas, chlamydiae • Second line agent for tuberculosis • Moxifloxacin fourth generation • F 90% t ½ 12~15h • High activity on most G+ ,G-, anaerobes, mycobateria, mycoplasmas, chlamydiae • Low toxicity

  34. Sulfonamides

  35. Sulfonamides • Classification • Used in systemic infections • Short-acting: SIZ • Medium-acting: SD, SMZ • Long-acting: SMD • Used in intestinal infections: sulfasalazine • Topic sulfonamides: SD-Ag, SA-Na, SML

  36. Sulfonamides • Antimicrobial activity • Broad-spectrum bacteriostatic agents • Both G+ and G- , chlamydiae trachomatis mycoplasm and some protozoa • Mechanism of action • Inhibit dihydropteroate synthetaseand block bacteria folic acid synthesis

  37. Sulfonamides • Pharmacokinetics • Metabolism: liver • Excretion : kidney pH

  38. Sulfonamides • Adverse effects • Urinary tract disturbance: crystalluria, hematuria, obstruction • Allergic reactions: fever, skin rashes, exfoliative dermatitis, photosensitivity • Hematopoietic disturbances • Granulocytopenia, thrombocytopenia • Hemolytic reactions lack of glucose-6-phosphate dehydrogenase • CNS reaction: headache, vertigo

  39. Sulfonamides • Clinical uses • Urinary tract infection: SIZ, SMZ • Meningococcal meningitis: SD first choice • Ulcerative colitis: sulfasalazine(SASP) • Bacterial dysentery: SMZ • Topical use for trachoma and conjunctivitis: SA-Na • Prevent infections of burn wounds: SD-Ag, SML

  40. Trimethoprim （TMP） • Inhibit bacterial dihydrofolate reductase • Used in combination with sulfonamides: synergism • SMZ+TMP (SMZco,复方新诺明) • Toxicity: teratogenesis

  41. Nitrofurans • Nitrofurantoin • Low blood concentration • Urinary tract infection • Furazolidone • Poorly absorbed • Gastrointestinal tract infection • H.p infection

  42. Metronidazole • Antimicrobial activity and clinical uses • Extraluminal amebiasis: drug of choice • Infections caused by anaerobes • Giardiasis • Trichomoniasis • H.p infection

  43. Metronidazole • Adverse reactions • Gastrointestinal irritation: metallic taste in mouth, nausea, dry mouth • Disulfiram-like effect • CNS: vertigo, parensthesias, ataxia and seizures • Mutagenic and carcinogenic

  44. Tinidazole (替硝唑） • Higher activity 2 • Good pharmacokinetics • Long t 1/2 • Penetrate tissue well • High concentration in CSF 88% • Less toxicity

  45. THE END

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