1、Chapter 42 Tetracyclines and Chloramphenicol,Tetracyclines,Natural: Tetracycline, oxytetracycline, chlortetracycline Semi-synthesizedDoxycycline and minocycline,Tetracyclines,Antimicrobial activity Broad-spectrum bacteriostatic antibiotics Many gram-positive and gram-negative bacteria including anae
2、robes Rickettsiae, chlamydiae and mycoplasm Some protozoa: amebas,Tetracyclines,Mechanism of actionTetracyclines 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.,Tetracyclines,Resistance Product
3、ion of an efflux pump Ribosome protection due to production of proteins that interfere with tetracyclines binding to the ribosome Production of enzyme,Tetracycline,Pharmacokinetics Absorption: affected by food ,divalent cations（Ca2+, Mg2+ , Fe2+ ）, dairy products and antiacid Distribution: distribut
4、e 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,Tetracyclines,Clinical usesRickettsiae infections : first choice Chlamydiae pneumoniae Mycoplasma infection Relapsing fever: the most effe
5、ctive Various gram-positive and negative infections Gastric ulcer and duodenal ulcer caused by Helicobacter pylori in combination regimens,Tetracycline,Adverse reactions Gastrointestinal adverse effects Superinfection Pseudomembranous enterocolitis caused by clostridium difficile Candida albicans in
6、fection Effects on bony structure and teeth Teeth: fluorescence, discoloration and enamel dysplasia Bone: deformity or growth inhibition Liver and kidney toxicity, photosensitization,Synthesized tetracyclines,Doxycycline and minocycline Almost completely absorbed Long-acting: t 1/2 14h Higher activi
7、ty than tetracycline Effective against tetracycline-resistant bacteria Low toxicity Minocycline: the strongest activity/ vestibular disturbance,Chloramphenicol,Antimicrobial activity,Broad-spectrum bacteriostatic antibiotics Both gram-positive and gram-negative aerobic and anaerobic organisms Ricket
8、tsiae, spirochetes, mycoplasm,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,Pharmacokinetics,Absorption : po High concentration in CSF Metaboliz
9、ed in liver,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,Adverse reactions,Bone marrow disturbances Reversible suppressi
10、on of RBC production Ireversible aplastic anemiaGray baby syndromedose 50mg/kg/d Gastrointestinal reactions,Chapter 43 Synthetic organic antimicrobials,Synthetic organic antimicrobials,Quinolones Sulfonamides Trimethoprim（TMP） Nitrofurans Metronidazole,Quinolones,Brief introduction Antibacterial act
11、ivity Mechanism of action Clinical uses Adverse reactions,Brief introduction of quinolones,Four generations First generation:1962 Lesher nalidixic acid Second generation: 1973 pipemidic acid Third generation: 1980s fluoroquinolones Fourth generation: late 1990s moxifloxacin（莫西沙星）, gatifloxacin(加替沙星)
12、,Nalidixic acidfirst generation,Narrow antibacterial spectrum:G- Poorly absorbed High adverse reactions,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,Fluor
13、oquinolonesthird 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,Fluoroquinolones,Antibacterial activity： broad spectrum Excellent activity against gram-negative aerobic bacteria include enterobacteriaceae, neisseria
14、, 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,Quinolones,Mechanism of action To G-: DNA gyrase A2B2 To G+: Topo C2E2 Re
15、sistance Mutation of target : gyrA or parC Lack of OmpF on membrane Active efflux pump,Fluoroquinolones,Pharmacokinetics Absorbed rapidly and completely Widely distributed Long T Low adverse reaction No cross-resistance with other drugs,Fluoroquinolones,Clinical uses Urinary and genital tract infect
16、ions 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,Fluoroquinolones,Adverse reactions Gastrointestinal reaction: nausea, v
17、omiting and diarrhea CNS: headache, dizziness, insomnia and anxiety, seizure Allergic effect: skin rash, photosensitivity Damage growing cartilage and cause arthropathy,Contradications,Pregnancy Children CNS disorder History of epilepsy Allergic,Commonly used Quinolones,Nalidixic acid and pipemidic
18、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-negat
19、ives, particularly P. aeruginosa in vitro No effects on anaerobes,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 ag
20、ainst gram-positive organisms Effective on mycoplasma, legionella, chlamydia and anaerobes Lowest toxicity among fluoroquinolones,Lomefloxacin: F 98% t = 7h To G+ and G-: Similar to ofloxacin To anaerobes: 10h Higher activity than ciprofloxacin and ofloxacin(in vivo),Sparfloxacin Long-acting t 16h I
21、mproved activity against G+ bacteria, anaerobes, mycobateria, mycoplasmas, chlamydiae Second line agent for tuberculosis Moxifloxacin fourth generationF 90% t 1215h High activity on most G+ ,G-, anaerobes, mycobateria, mycoplasmas, chlamydiae Low toxicity,Sulfonamides,Sulfonamides,Classification Use
22、d 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,Sulfonamides,Antimicrobial activity Broad-spectrum bacteriostatic agents Both G+ and G- , chlamydiae trachomatis mycoplasm and some pr
23、otozoa Mechanism of action Inhibit dihydropteroate synthetase and block bacteria folic acid synthesis,Sulfonamides,PharmacokineticsMetabolism: liverExcretion : kidney pH,Sulfonamides,Adverse effects Urinary tract disturbance: crystalluria, hematuria, obstruction Allergic reactions: fever, skin rashe
24、s, exfoliative dermatitis, photosensitivity Hematopoietic disturbances Granulocytopenia, thrombocytopenia Hemolytic reactionslack of glucose-6-phosphate dehydrogenaseCNS reaction: headache, vertigo,Sulfonamides,Clinical uses Urinary tract infection: SIZ, SMZ Meningococcal meningitis: SD first choice
25、 Ulcerative colitis: sulfasalazine(SASP) Bacterial dysentery: SMZ Topical use for trachoma and conjunctivitis: SA-Na Prevent infections of burn wounds: SD-Ag, SML,Trimethoprim （TMP）,Inhibit bacterial dihydrofolate reductase Used in combination with sulfonamides: synergism SMZ+TMP (SMZco,复方新诺明) Toxic
26、ity: teratogenesis,Nitrofurans,Nitrofurantoin Low blood concentration Urinary tract infection Furazolidone Poorly absorbed Gastrointestinal tract infection H.p infection,Metronidazole,Antimicrobial activity and clinical uses Extraluminal amebiasis: drug of choice Infections caused by anaerobes Giard
27、iasis Trichomoniasis H.p infection,Metronidazole,Adverse reactions Gastrointestinal irritation: metallic taste in mouth, nausea, dry mouth Disulfiram-like effect CNS: vertigo, parensthesias, ataxia and seizures Mutagenic and carcinogenic,Tinidazole (替硝唑）,Higher activity 2 Good pharmacokineticsLong t 1/2 Penetrate tissue wellHigh concentration in CSF 88% Less toxicity,THE END,
