第四十三章人工合成抗菌药.ppt

1、人工合成抗菌药,Synthesized Antibacterial Agents,Antibacterial Agents III,分 类,喹诺酮类：诺氟沙星（norfloxacin） 磺胺类：磺胺嘧啶(sulfadiazine) 甲氧苄啶类：甲氧苄啶(trimethoprim) 硝基呋喃类：呋喃妥因(nitrofurantoin) 硝咪唑类：甲硝唑(metronidazole),第一节 喹诺酮类药物 Quinolones,Fluoroquinolones,喹诺酮类发展简史,1962年Lesher 发现萘啶酸 1974年吡哌酸 1979年诺氟沙星 一系列氟喹诺酮类,Ciprofloxacin,

2、Levofloxacin,概 述,喹诺酮类是含有4-喹诺酮母核基本结构的合成抗菌药,4-喹诺酮化构中引入基团与抗菌效果的关系,抗菌机制,抑制DNA回旋酶而影响细菌DNA的合成。,Structure of bacterial DNA gyrase complexed with DNA and two ciprofloxacin molecules (green),氟喹诺酮类药理学特性,抗菌谱 体内过程 临床应用 不良反应 耐药性,不 良 反 应,1. 氟喹诺酮类影响骨骼发育，孕妇及婴幼儿慎用 2. 因其引起中枢神经系统不良反应，故有神经系统病史者慎用 3. 可引起变态反应，有过敏史者禁用或慎用

3、4. 其抑制茶碱、口服抗凝药的肝中代谢，应避免与之合用; 与制酸药合用，可减少其吸收 5. 多数药物主要经肾排泄，肾功能减退时，应注意调整剂量,第二节 磺胺类药和甲氧苄啶Sulfonamides,磺胺类药物是三十年代发现的能有效防治全身性细菌感染的第一类化疗药物。,对氨基苯磺酰胺,荣获1939年诺贝尔生理学或医学奖 发现了百浪多息的抗菌作用,杜马克 Gerhard Domagk 德国 慕斯特大学 1895年-1964年,分 类,抗菌机制,抗菌谱,G+球菌：对溶血性链球菌、肺炎球菌敏感 G-球菌：脑膜炎奈瑟菌、淋病奈瑟菌有效 杆菌：大肠埃希菌、布鲁斯菌、变形杆菌等 衣原体 放线菌 伤寒 疟原虫,

4、磺胺嘧啶（SD）,体内过程 （1）在脑脊液中浓度高，与血浆蛋白 结合率低 （2）肝代谢 （3）肾脏排泄 （4）肠道难吸收的随粪便排泄,2. 应用,易通过血脑屏障,抑制脑膜炎奈瑟菌,（1）流脑,（2）泌尿道、呼吸道感染 （3）丹毒、蜂窝组织炎,3.不良反应,（1）损害泌尿系统 （2）抑制造血系统 （3）过敏反应,甲氧苄啶类（TMP）,作用机制,二氢叶酸还原酶,二氢叶酸还原成四氢叶酸,核酸合成,甲氧苄啶,抗菌机制,2.临床应用,硝基呋喃类药物 Nitrofurans,呋喃妥因(nitrofurantoin，呋喃坦啶) 呋喃唑酮(furazolidone，痢特灵),硝基咪唑类药物 Nitroimid

5、azoles,甲硝唑(metronidazole, 甲硝哒唑, 灭滴灵),抗菌药物作用机制示意图,Clinical Use of antibacterial agents,Community-acquired Shigella N.gonorrhea H.influenzae M.catarrhalis S.pneumoniae Hospital-acquired S.aureus VRSA Enterococci Enterobacteriaceae,MRSA,VRE,ESBL,Major resistance problems,1940 1950 1960 1970 1980 1990 2

6、000,MRSA HA vs. CA,Community acquired (CA) MRSA Younger population. More likely to produce skin and soft tissue infections. Not multi-drug resistant. Healthcare associated (HA) MRSA Multi-drug resistant. Associated with foreign bodies.,Multidrug resistanceis a condition enabling a disease-causing or

7、ganism to resist distinct drugs or chemicals of a wide varietyof structure and function targeted at eradicating the organism.,Treatment,Vancomycin Clindamycin Bactrim Tetracycline Combination therapy,Principles of antibacterial use,Basic principles Diagnosis Rational use Newborn Pregnancy Elderly,Sy

8、nergetic mechanism of combination antibacterial therapy,Affect different component of the same mechanism Changing the permeability of the cytoplasmic membrane or the cell wall Inhibiting the inactiving enzyme of antibacterial drugs Inhibiting the different resistant microbial population,Principles o

9、f antibacterial use,Antimicrobial agents combination Drug categories 1.-Lactam antibiotics 2. Aminoglycosides 3. Tetracyclines, macrolide, chloramphenicol 4. Sulfonamides 1+2: Synergism 1+3:antagonism 2+3:synergism or plus 3+4: plus,Rationale for combination antibacterial therapy,To Provide broad-sp

10、ectrum therapy in seriously ill patients Serious infection that can not be controlled by one drug To decrease the emergence of resistant strains To decrease dose-related toxicity Meningitis and osteomyelitis caused by bacterial infection,Principles of antibacterial use,Misuse Virus infection Unknown

11、 fever Topical use Improper prophylaxis and combination,Antimicrobials are routinely added to animal feed and water to promote animal growth. -Rationale is to promote more rapid growth reducing farming expenses. -Mechanisms are debated although most commonly invoked is the reduction of infections, especially in