抗菌药物概论
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抗菌药物概论. 常用术语 抗菌药物作用机制 抗菌药物的耐药性 抗菌药物的合理应用 药物滥用与食品安全. I. Chemotherapy. The Birth of Modern Chemotherapy: Dreams of a “Magic Bullet”. Louis Pasteur 1822-1895. Robert Koch 1843-1910. Rebecca Lancefield 1896-1981. I. Chemotherapy.

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抗菌药物概论

常用术语

抗菌药物作用机制

抗菌药物的耐药性

抗菌药物的合理应用

药物滥用与食品安全


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I. Chemotherapy

The Birth of Modern Chemotherapy: Dreams of a “Magic Bullet”

Louis Pasteur 1822-1895

Robert Koch 1843-1910

Rebecca Lancefield 1896-1981


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I. Chemotherapy

  • 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

1928 Fleming discovers penicillin


History of antimicrobial therapy
History of Antimicrobial Therapy

I. Chemotherapy

1928


History of antimicrobial therapy1
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 therapy2
History of Antimicrobial Therapy

I. Chemotherapy

Endless way ………………

MRSA,NAM-1

Superbug……drug resistance



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II. Chemotherapeutic agents

Host Factors: patient’s age, gender, constitution, hepatic, renal function

Adverse effects

Resistance

Pharmacokinetics

Therapeutic Effects

pathogenicity

Immunological

responses


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II. Chemotherapeutic agents

Ideal antimicrobial drugs

  • High sensitivity

  • Nontoxic or low-toxic (safety)

  • Nonresistance

  • Satisfied pharmacokinetic properties

  • Good price


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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


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Antibacterial spectrum(抗菌谱)

Narrow?

Broad?

Chemotherapetic index (CI)(化疗指数)

CI= LD50 / ED50

CI= LD5 / ED95

II. Chemotherapeutic agents


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II. Chemotherapeutic agents

  • Bacteriostatic drugs (抑菌药)

  • inhibit the growth of microorganisms

  • e.g. Sulfonamides, Tetracycline

  • Bactericidal drugs (杀菌药)

  • kill microorganisms

  • e.g. Penicillin, Aminoglycosides


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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


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II. Chemotherapeutic agents

最低抑菌浓度

最低杀菌浓度


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II. Chemotherapeutic agents

Incubate 18 to

24 hr at 37℃

Measure

diameters of

nongrowth

zones

Disk diffusion method for testing bacteria for susceptibility to specific antimicrobial drugs.




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Intrinsic resistance

– Inherent features ,usually expressed by

chromosomal genes

Acquired resistance

– Emerge from previously sensitive bacterial

populations

– Caused by mutations in chromosomal

genes

– Or by acquisition of plasmids or

transposons

IV. Bacterial Resistance


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The drug is not active.

The target is altered.

The drug does not reach its target.

IV. Bacterial Resistance

Bacterial Resistance- Mechanisms


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Production of aminoglycoside-modifying enzymes and b-lactamase;

IV. Bacterial Resistance

1.The drug is not active.


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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)


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Target modification (ribosomal protection type of resistance to macrolides and tetracyclines)

IV. Bacterial Resistance

2.The target is altered


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Absence, mutation or loss of the appropriate to macrolides and tetracyclines)transporteror porins (膜孔蛋白)

IV. Bacterial Resistance

3.The drug does not reach its target


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Active efflux system to macrolides and tetracyclines)(主动排出系统)

Efflux transporter(转运子)

Accessory protein (附加蛋白)

Outer membrane channel(外膜蛋白)

IV. Bacterial Resistance

3.The drug does not reach its target


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Active efflux system to macrolides and tetracyclines)(主动排出系统 )

IV. Bacterial Resistance

Outer membrane

channel

Accessory protein

transporter


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Mutations to macrolides and tetracyclines)突变

Transduction 转导

Transformation 转化

Conjugation 接合

IV. Bacterial Resistance

The transfer of Resistance genes

  • From human  human

  • From bacteria  bacteria

  • Intracellular


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Mutations to macrolides and tetracyclines)突变

IV. Bacterial Resistance


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Transduction to macrolides and tetracyclines)转导

IV. Bacterial Resistance


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Transformation to macrolides and tetracyclines)转化

IV. Bacterial Resistance

  • Conjugation 接合


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IV. Bacterial Resistance to macrolides and tetracyclines)

Multi-drug resistance (MDR)

  • Methicillin-resistant staphylococcus aureus, MRSA

  • 甲氧西林耐药金黄色葡萄球菌

  • Methicillin-resistant coagulase

  • negative staphylococci, MRCNS

  • 甲氧西林凝固酶阴性葡萄球菌

  • PBP-2a (a 78kD new PBP)


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IV. Bacterial Resistance to macrolides and tetracyclines)

Multi-drug resistance MDR

  • Penicillin-resistant streptococcus pneumoniae,

  • PRSP,青霉素耐药肺炎链球菌

  • PBP-1a, PBP-2a, PBP-2x, PBP-2b (78-100 kD)

  • Active efflux system (express mef(A)对大环内酯类)

  • Vancomycin-resistant Enterococcus, VRE

  • 万古霉素耐药肠球菌

  • PBP avidity ↓

  • van-A, van-B, van C-1, van C-2, van D, van E


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IV. Bacterial Resistance to macrolides and tetracyclines)

Multi-drug resistance MDR

  • 4. The 3rd generation-cephalosporins -resistant

  • Extended spectrumβ-lactamases, ESBL

  • 超广谱β- 内酰胺酶

  • Class I chromosone mediated β-lactamases

  • 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


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IV. Bacterial Resistance to macrolides and tetracyclines)

Multi-drug resistance MDR

  • Carbapenem (碳青霉烯) –resistant:对亚胺培南的铜绿假单胞菌敏感

  • OprD porin

  • Metalβ-lactamases (金属β- 内酰胺酶)

  • 6. Quinolone-resistant escherichia coli(大肠埃希菌), AREC

  • Active efflux system

  • Cross-resistance

superbug or super bacterium


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Basic principle of clinical usage of antimicrobial agents to macrolides and tetracyclines)

Antimicrobial drugs -Characteristics

Some laboratory techniques that are useful in the diagnosis of microbial diseases


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According to bio-activity to macrolides and tetracyclines)

Anti G+ antibiotic

Anti G- antibiotic

Broad-spectrum antibiotic

Anti mycobacterium antibiotic

Anti anaerobe antibiotic

- lactamase inhibitor

Basic principle of clinical usage of antimicrobial agents

Antimicrobial drugs -Characteristics


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According to the chemical structure to macrolides and tetracyclines):

-lactams (-内酰胺类);Penicillins(青霉素类);Cephalosporins(头孢菌素类);

Aminoglycosides(氨基糖苷类);

Macrolides(大环内酯类); Lincosamides(林可胺类);Vancomycins(万古霉素类)

Tetracyclines(四环素类);

Chloramphenicol (氯霉素)

Basic principle of clinical usage of antimicrobial agents

Antimicrobial drugs -Characteristics


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5. Quinolones ( to macrolides and tetracyclines)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)

Streptogramins(链阳菌素类)

Basic principle of clinical usage of antimicrobial agents


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参考书目: to macrolides and tetracyclines)


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