第四十三章人工合成抗菌藥

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,

2、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,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 b

3、acterial 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

4、引起變態(tài)反應(yīng)，有過敏史者禁用或慎用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德國慕斯特

5、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,磺胺嘧啶（SD）,體內(nèi)過程 （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,,易通過血腦屏障,抑制腦膜炎奈瑟菌,（1）流腦,

6、（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 Nitroimidazoles,甲硝唑(

7、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

8、 H.influenzae M.catarrhalis S.pneumoniaeHospital-acquired S.aureus

9、 VRSA Enterococci Ent

10、erobacteriaceae,,,,,,,,MRSA,,,,,,VRE,ESBL,,,,,,,,,Major resistance problems,1940 1950 1960 1970 1980 1990 2000,MRSA – HA vs. CA,Community acquired (CA) MRSAYou

11、nger population.More likely to produce skin and soft tissue infections.Not multi-drug resistant.Healthcare associated (HA) MRSAMulti-drug resistant.Associated with foreign bodies.,Multidrug resistance is a cond

12、ition enabling a disease-causing organism to resist distinct drugs or chemicals of a wide variety of structure and function targeted at eradicating the organism.,Treatment,VancomycinClindamycinBactrimTetracycline

13、Combination therapy,Principles of antibacterial use,Basic principlesDiagnosis Rational useNewbornPregnancy Elderly,Synergetic mechanism of combination antibacterial therapy,Affec

14、t different component of the same mechanismChanging the permeability of the cytoplasmic membrane or the cell wallInhibiting the inactiving enzyme of antibacterial drugsInhibiting the different resistant microbial pop

15、ulation,Principles of antibacterial use,Antimicrobial agents combinationDrug categories1.β-Lactam antibiotics2. Aminoglycosides3. Tetracyclines, macrolide, chloramphenicol4. Sulfonamides1+2: Synergism1+3:antagoni

16、sm2+3:synergism or plus3+4: plus,Rationale for combination antibacterial therapy,To Provide broad-spectrum therapy in seriously ill patientsSerious infection that can not be controlled by one drugTo decrease the em

17、ergence of resistant strainsTo decrease dose-related toxicityMeningitis and osteomyelitis caused by bacterial infection,Principles of antibacterial use,MisuseVirus infectionUnknown feverTopical useImproper prophyla

18、xis 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

19、most commonly invoked is the reduction of infections, especially in unsanitary conditions.Many of the antibiotics used in this setting are of the same class as those used to treat human infections. --macrolides, tet