1、人工合成抗菌藥,Synthesized Antibacterial Agents,Antibacterial Agents III,分 類,喹諾酮類：諾氟沙星（norfloxacin） 磺胺類：磺胺嘧啶(sulfadiazine) 甲氧芐啶類：甲氧芐啶(trimethoprim) 硝基呋喃類：呋喃妥因(nitrofurantoin) 硝咪唑類：甲硝唑(metronidazole),第一節(jié) 喹諾酮類藥物 Quinolones,Fluoroquinolones,喹諾酮類發(fā)展簡(jiǎn)史,1962年Lesher 發(fā)現(xiàn)萘啶酸 1974年吡哌酸 1979年諾氟沙星 一系列氟喹諾酮類,Ciprofloxacin,

2、Levofloxacin,概 述,喹諾酮類是含有4-喹諾酮母核基本結(jié)構(gòu)的合成抗菌藥,4-喹諾酮化構(gòu)中引入基團(tuán)與抗菌效果的關(guān)系,抗菌機(jī)制,抑制DNA回旋酶而影響細(xì)菌DNA的合成。,Structure of bacterial DNA gyrase complexed with DNA and two ciprofloxacin molecules (green),氟喹諾酮類藥理學(xué)特性,抗菌譜 體內(nèi)過(guò)程 臨床應(yīng)用 不良反應(yīng) 耐藥性,不 良 反 應(yīng),1. 氟喹諾酮類影響骨骼發(fā)育，孕婦及嬰幼兒慎用 2. 因其引起中樞神經(jīng)系統(tǒng)不良反應(yīng)，故有神經(jīng)系統(tǒng)病史者慎用 3. 可引起變態(tài)反應(yīng)，有過(guò)敏史者禁用或慎用

3、4. 其抑制茶堿、口服抗凝藥的肝中代謝，應(yīng)避免與之合用; 與制酸藥合用，可減少其吸收 5. 多數(shù)藥物主要經(jīng)腎排泄，腎功能減退時(shí)，應(yīng)注意調(diào)整劑量,第二節(jié) 磺胺類藥和甲氧芐啶Sulfonamides,磺胺類藥物是三十年代發(fā)現(xiàn)的能有效防治全身性細(xì)菌感染的第一類化療藥物。,對(duì)氨基苯磺酰胺,榮獲1939年諾貝爾生理學(xué)或醫(yī)學(xué)獎(jiǎng) 發(fā)現(xiàn)了百浪多息的抗菌作用,杜馬克 Gerhard Domagk 德國(guó) 慕斯特大學(xué) 1895年-1964年,分 類,抗菌機(jī)制,抗菌譜,G+球菌：對(duì)溶血性鏈球菌、肺炎球菌敏感 G-球菌：腦膜炎奈瑟菌、淋病奈瑟菌有效 桿菌：大腸埃希菌、布魯斯菌、變形桿菌等 衣原體 放線菌 傷寒 瘧原蟲,

4、磺胺嘧啶（SD）,體內(nèi)過(guò)程 （1）在腦脊液中濃度高，與血漿蛋白 結(jié)合率低 （2）肝代謝 （3）腎臟排泄 （4）腸道難吸收的隨糞便排泄,2. 應(yīng)用,易通過(guò)血腦屏障,抑制腦膜炎奈瑟菌,（1）流腦,（2）泌尿道、呼吸道感染 （3）丹毒、蜂窩組織炎,3.不良反應(yīng),（1）損害泌尿系統(tǒng) （2）抑制造血系統(tǒng) （3）過(guò)敏反應(yīng),甲氧芐啶類（TMP）,作用機(jī)制,二氫葉酸還原酶,二氫葉酸還原成四氫葉酸,核酸合成,甲氧芐啶,抗菌機(jī)制,2.臨床應(yīng)用,硝基呋喃類藥物 Nitrofurans,呋喃妥因(nitrofurantoin，呋喃坦啶) 呋喃唑酮(furazolidone，痢特靈),硝基咪唑類藥物 Nitroimid

5、azoles,甲硝唑(metronidazole, 甲硝噠唑, 滅滴靈),抗菌藥物作用機(jī)制示意圖,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