常用术语 常用术语 抗菌药物作用机制 抗菌药物作用机制 抗菌药物的耐药性 抗菌药物的耐药性 抗菌药物的合理应用 抗菌药物的合理应用 药物滥用与食品安全 药物滥用与食品安全 抗菌药物概论

The Birth of Modern Chemotherapy: Dreams of a “Magic Bullet” I. Chemotherapy Louis Pasteur Robert Koch Rebecca Lancefield

Paul Ehrlich introduced an arsenic-containing chemical called salvarsan （阿斯凡纳明） to treat syphilis （梅毒） (1910). –“Magic bullet” for treatment of syphilis I. Chemotherapy 1928 Fleming discovers penicillin

History of Antimicrobial Therapy I. Chemotherapy 1928

History of Antimicrobial Therapy 1928 Fleming discovers penicillin ( 青霉素 ) 1932 Domagk discovers sulfonamides （磺胺类） 1940s Penicillin and streptomycin （链霉素） used widely, cephalosporins （头孢霉素） discovered 1947 Chloramphenicol （氯霉素） discovered, first broad spectrum agent 1950s Tetracycline （四环素） in use 1952 Erythromycin （红霉素） discovered (macrolides ，大环内脂类 ) 1956 Vancomycin （万古霉素） used for penicillin-resistant S. aureus 1957 Kanamycin （卡那霉素） discovered (aminoglycosides ，氨基 糖苷类 ) 1962 Nalidixic acid （奈啶酸） discovered (quinolones ，喹诺酮类 ) 1980s Fluoroquinolones （氟喹诺酮）, broad spectrum cephalosporins （广谱头孢类） 2000s Newer agents to combat resistant pathogens I. Chemotherapy

History of Antimicrobial Therapy I. Chemotherapy Endless way ……………… Superbug……drug resistance MRSA ， NAM-1

II. Chemotherapeutic agents

Pharmacokinetics Adverse effects pathogenicity Immunologicalresponses Therapeutic Effects Resistance Host Factors ： patient’s age, gender, constitution, hepatic, renal function II. Chemotherapeutic agents

Ideal antimicrobial drugs  High sensitivity  Nontoxic or low-toxic (safety)  Nonresistance  Satisfied pharmacokinetic properties  Good price II. Chemotherapeutic agents

Antibacterial drugs ( 抗菌药 )  kill bacteria and arresting its growth  Antibiotics( 抗生素 ) and synthetic antimicrobial agents( 人工合成抗 菌药物 ) such as sulfonamides( 磺胺类 ) and quinolones ( 喹诺酮类 ). Antibiotics ( 抗生素 )  Produced by various species of microorganisms (bacteria, fungi, actinomycetes), such as penicillin ( 青霉素 )  Suppress the growth of other microorganisms. II. Chemotherapeutic agents

Antibacterial spectrum （抗菌谱） Narrow?Narrow? Broad?Broad? Chemotherapetic index (CI) （化疗指数） CI= LD 50 / ED 50CI= LD 50 / ED 50 CI= LD 5 / ED 95CI= LD 5 / ED 95 II. Chemotherapeutic agents

Bacteriostatic drugs （抑菌药） inhibit the growth of microorganisms e.g. Sulfonamides, Tetracycline Bactericidal drugs （杀菌药） kill microorganisms kill microorganisms e.g. Penicillin, Aminoglycosides II. Chemotherapeutic agents

Minimum inhibitory concentration (MIC) 最低抑菌浓度 Minimum bactericidal concentration (MBC) 最低杀菌浓度 Post antibiotic effect (PAE) 抗生素后效应 Resistance （耐药性） Cross Resistance （交叉耐药性） First expose effect （首次接触效应） II. Chemotherapeutic agents

最低抑菌浓度 最低杀菌浓度

Incubate 18 to 24 hr at 37 ℃ Measure diameters of nongrowthzones Disk diffusion method for testing bacteria for susceptibility to specific antimicrobial drugs. II. Chemotherapeutic agents

III. Mechanism of action

IV. Bacterial Resistance

 Intrinsic resistance – Inherent features ， usually expressed by – Inherent features ， usually expressed by chromosomal genes chromosomal genes  Acquired resistance – Emerge from previously sensitive bacterial – Emerge from previously sensitive bacterial populations populations – Caused by mutations in chromosomal – Caused by mutations in chromosomal genes genes – Or by acquisition of plasmids or – Or by acquisition of plasmids or transposons transposons IV. Bacterial Resistance

The drug is not active. The drug is not active. The target is altered. The target is altered. The drug does not reach its target. The drug does not reach its target. Bacterial Resistance- Mechanisms IV. Bacterial Resistance

 Production of aminoglycoside-modifying enzymes and  -lactamase; 1.The drug is not active. IV. Bacterial Resistance

2.The target is altered Mutation of the natural target (quinolone resistance) Substitution with a resistant alternative to the native, susceptible target (methicillin 甲氧西林 resistance) IV. Bacterial Resistance

Target modification (ribosomal protection type of resistance to macrolides and tetracyclines) 2.The target is altered IV. Bacterial Resistance

Absence, mutation or loss of the appropriate transporter or porins ( 膜孔蛋白） 3.The drug does not reach its target IV. Bacterial Resistance

Active efflux system ( 主 动排出系统 )  Efflux transporter （转运子）  Accessory protein （附加蛋白）  Outer membrane channel （外膜蛋白） 3.The drug does not reach its target IV. Bacterial Resistance

Active efflux system （主动排出系统 ） transporter Accessory protein Outer membrane channel IV. Bacterial Resistance

 Mutations 突变  Transduction 转导  Transformation 转化  Conjugation 接合 The transfer of Resistance genes IV. Bacterial Resistance  From human  human  From bacteria  bacteria  Intracellular

Mutations 突变 IV. Bacterial Resistance

Transduction 转导 IV. Bacterial Resistance

Transformation 转化Transformation 转化 Conjugation 接合Conjugation 接合 IV. Bacterial Resistance

Multi-drug resistance (MDR) 1.Methicillin-resistant staphylococcus aureus, MRSA 甲氧西林耐药金黄色葡萄球菌 甲氧西林耐药金黄色葡萄球菌 Methicillin-resistant coagulase Methicillin-resistant coagulase negative staphylococci, MRCNS negative staphylococci, MRCNS 甲氧西林凝固酶阴性葡萄球菌 甲氧西林凝固酶阴性葡萄球菌 PBP-2a （ a 78kD new PBP ） PBP-2a （ a 78kD new PBP ） IV. Bacterial Resistance

Multi-drug resistance MDR 2.Penicillin-resistant streptococcus pneumoniae, PRSP ，青霉素耐药肺炎链球菌 PRSP ，青霉素耐药肺炎链球菌 PBP-1a, PBP-2a, PBP-2x, PBP-2b （ kD ）PBP-1a, PBP-2a, PBP-2x, PBP-2b （ kD ） Active efflux system （ express mef(A) 对大环内酯类）Active efflux system （ express mef(A) 对大环内酯类） 3.Vancomycin-resistant Enterococcus, VRE 万古霉素耐药肠球菌 万古霉素耐药肠球菌 PBP avidity ↓PBP avidity ↓ van-A, van-B, van C-1, van C-2, van D, van Evan-A, van-B, van C-1, van C-2, van D, van E IV. Bacterial Resistance

4. The 3 rd generation-cephalosporins -resistant Extended spectrumβ-lactamases, ESBLExtended spectrumβ-lactamases, ESBL 超广谱 β- 内酰胺酶 超广谱 β- 内酰胺酶 Class I chromosone mediated β-lactamasesClass I chromosone mediated β-lactamases I 类染色体介导的 β- 内酰胺酶 I 类染色体介导的 β- 内酰胺酶 E.g. 大肠埃希菌、克雷伯肺炎杆菌、阴沟肠杆菌E.g. 大肠埃希菌、克雷伯肺炎杆菌、阴沟肠杆菌 Multi-drug resistance MDR IV. Bacterial Resistance

5.Carbapenem ( 碳青霉烯 ) –resistant ：对亚胺培 南的铜绿假单胞菌敏感 OprD porinOprD porin Metalβ-lactamases （金属 β- 内酰胺酶）Metalβ-lactamases （金属 β- 内酰胺酶 ） 6. Quinolone-resistant escherichia coli （大肠 埃希菌）, AREC Active efflux systemActive efflux system Cross-resistanceCross-resistance Multi-drug resistance MDR IV. Bacterial Resistance superbug or super bacterium

Antimicrobial drugs -Characteristics Basic principle of clinical usage of antimicrobial agents Some laboratory techniques that are useful in the diagnosis of microbial diseases

According to bio-activity  Anti G + antibiotic  Anti G - antibiotic  Broad-spectrum antibiotic  Anti mycobacterium antibiotic  Anti anaerobe antibiotic   - lactamase inhibitor Antimicrobial drugs -Characteristics Basic principle of clinical usage of antimicrobial agents

According to the chemical structure ： 1.  -lactams (  - 内酰胺类）； Penicillins （青霉素 类）； Cephalosporins （头孢菌素类） ; 2. Aminoglycosides( 氨基糖苷类 ); 3. Macrolides （大环内酯类） ; Lincosamides （林可胺类） ;Vancomycins （万古霉素类） 4. Tetracyclines （四环素类）； Chloramphenicol ( 氯霉素 ) Chloramphenicol ( 氯霉素 ) Antimicrobial drugs -Characteristics Basic principle of clinical usage of antimicrobial agents

5. Quinolones ( 喹诺酮类 ) 6. Sulphonamides ( 磺胺类 ) 7. Nitrofurans ( 硝基呋喃类 ) 8. Antimycobacterial agents ( 抗结核分 支杆菌类 ) 9. others: Oxazolidinones （恶唑烷酮类） Oxazolidinones （恶唑烷酮类） Streptogramins （链阳菌素类） Streptogramins （链阳菌素类） Basic principle of clinical usage of antimicrobial agents

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