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β-lactam antibiotics (β- 内酰胺类抗生素)
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Penicillin nucleus. β- lactam is the square at the center.
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二十世纪十大分子 1900-1910: aspirin 1910-1920: isooctane (异辛烷,与汽车工业有关) 1920-1930: penicillin G 1930-1940: polyethene (英国 ICI 科学家偶尔得到, 1933 合 成, 1939 年应用。大量用于雷达 cable insulation ) 1940-1950: nylon 6,6 ( 用于二战,代替丝织物 ) 1950-1960: DNA 1960-1970: progestin (黄体激素, contraceptives ) 1970-1980: DDT (对鸟、动物有害) 1980-1990: fluoxetine, introduced by Eli Lilly in 1986. 到 当时为止处方最多的抗抑郁药,在 90 多个国家应用。 1990-2000: carbon nanotubes
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Penicillins (青霉素类)
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Natural penicillins Penicillin G Pharmacokinetics: destroyed easily by gastric acid distribution widely and 5% across BBB when in meningitis renal tubular excretion in prototype
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Antibacterial spectrum Antibacterial spectrum: Gram-positive cocci : Staphylococcus infections Gram-negative cocci: Staphylococcus pneumoniae infection Gram-positive bacilli: diphtheria (白喉), tetanus (破伤风) Leptospira (螺旋体) : leptospirosis (钩端螺 旋体病) Actinomycetes (放线菌): actinomycosis (放线菌病)
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淋病奈瑟菌
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放线菌
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放线菌病
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Mechanism of penicillin β-Lactam antibiotics work by binding to transpeptidase and then inhibiting the formation of peptidoglycan cross- links in the bacterial cell wall.
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Peptidoglycan (肽聚糖) is a 3D molecule Cross links are both horizontal and vertical between glycan chains stacked atop one another.
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Resistance to penicillins Structural changes of penicillin binding protein (PBP) naturally PBP production caused by sensitive or inter-bacterial gene recombination Decrease of porin Hydrolysis by β-lactamases
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Adverse effects Allergic reactions Allergic shock, 0.004% - 0.04% 10% cross-sensitivity between penicillin-derivatives, cephalosporins, and carbapenems Inquiring history of β-lactam antibiotics use (没有用 过青霉素要不要做皮试?) Skin test before use Seizure-like reaction when intrathecally administrated in large amount (>20000 U) (seizure model) (inhibition of GABA synthesis, …)
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Semi-synthetic penicillins Penicillin G Advantages disadvantages ---------------------- high efficacyacid-irresistant low toxicity β-lactamase-irresistant cheapnarrow spectrum easy to use high allergic reactions ----------------------
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6-aminopenicillanic acid (6-APA, 6- 氨基青霉烷酸)
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Semi-synthetic penicillins Penicillin V resists destruction by gastric juice (oral route OK) Still β-lactamase-irresistant Less efficient when penicillin G is effective
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Semi-synthetic penicillins β-lactamase-resistant penicillins flucloxacillin (氟氯西林 ), oxacillin( 苯唑西林 ), cloxacillin (氯唑西林) β-lactamase-resistant Less efficient when penicillin G is effective
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Semi-synthetic penicillins Wide-spectrum penicillins (广谱青霉素) Ampicillin (氨苄西林), amoxicillin (阿莫西 林) wide spectrum (inhibiting gram positive and negative bacteria) Acid-resistant β-lactamase-irresistant
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Semi-synthetic penicillins antipseudomonal penicillins (抗铜绿假单胞菌青 霉素) Carbenicillin (羧苄西林), ticacillin (替卡西 林), piperacillin (哌拉西林) Antipseudomonal β-lactamase-irresistant Less efficient when penicillin G is effective
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Semi-synthetic penicillins Anti-Gram negative bacterial penicillins (抗 G - 杆菌青霉素) Mecillinam (美西林), temocillin (替莫西林) β-lactamase resistant and effective against Gram negative bacteria
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Cephalosporins (头孢菌素类)
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1948 , Italian Giuseppe Brotzu Sardinia, sewer Cephalosporium acremonium ( 头孢菌) Culture effective against Salmonella typhi (伤寒沙门菌) Cephalosporin C isolated in Oxford, weak activity
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7-aminocephalosporanic acid ( 7-ACA, 7- 氨基头孢烯酸)
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cephalosporins General characters: Wide antibacterial spectrum High efficacy Low allergic rate Partial cross-sensitivity to penicillin (lesser from third generation on) Certain extent of β-lactamase resistance
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cephalosporins Classification, based mainly on antibacterial properties: First generation: cefazolin (头孢唑啉), cephalexin (头孢氨苄): potent against G + ; renal toxicity Second generation: cefuroxime (头孢呋辛), cefacolor (头孢克洛): against G + & G - ; low renal toxicity Third generation: ceftriaxone (头孢曲松), cefoperazone (头孢哌酮): less against G +, more potent against G - ; very low renal toxicity Fourth generation: cefepime (头孢吡肟) : potent both against G + & G - ; no renal toxicity 各代头孢菌素都在临床应用 !!!
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Carbapenems (碳青霉烯类)
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Other β-lactam penicillins Imipenem (亚胺培南)
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imipenem
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Imipenem 亚胺培南 extremely broad spectrum high efficacy β-lactamase resistant hydrolyzed easily by renal dehydropeptidase; co-administered with silastatin (西司他丁), the enzyme inhibitor
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Meropenem (美罗培南) Dehydropeptidase- resistant Even wider antibacterial spectrum than imipenem
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Cephamycins (头霉素类)
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Cephamycins ≈second generation of cephalosporin Cefoxitin 头孢西丁; Cefmetazole (头孢美唑)
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Oxacephems (氧头孢烯类)
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Latamoxef (拉氧头孢) wide antibacterial spectrum like third generation of cephalosporins Strong anti-anaerobic bacterial effect prolonged bleeding time (even lethal) No longer available in US
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Monocyclic β-lactam antibiotic 单环 β- 内酰胺抗生素
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Monocyclic β-lactam antibiotic strong activity against susceptible gram- negative bacteria including Pseudomonas aeruginosa. like aminoglycosides, but no renal toxicity Aztreonam 氨曲南
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β-lactamase inhibitors and compound preparation β- 内酰胺酶抑制剂及复方制剂
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Clavulanic acid 克拉维酸
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β-lactamase inhibitor clavulanic acid (克拉维酸) ; sulbactam (舒 巴坦); tazobactam (他唑巴坦) similarity in chemical structure allows the molecule to act as a competitive inhibitor of β-lactamases to confer β-lactam antibiotics antibacterial activity co-administered with β-lactam antibiotics: clavulanic acid + amoxicillin sulbactam + cefoperazone
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Glycopeptide antibiotics 糖肽类 and Other antibiotics
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Vancomycin (万古霉素) Borneo 婆罗洲丛林土 壤 Eli Lilly, EC Kornfeld
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vancomycin Glycopeptide; preventing incorporation of N-acetylmuramic acid (NAM)- and N- acetylglucosamine (NAG)-peptide subunits into the peptidoglycan matrix Only effective against gram + bacteria including MRSA Traditionally, drug of “last resort” VRSA: vancomycin-resistant Staphylococcus aureus VRE: vancomycin-resistant enterococci
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Scanning electron micrographs of vancomycin- resistant Enterococcus
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vancomycin Severe ototoxicity and nephrotoxicity, etc. being replaced by linezolid (利奈唑胺) and daptomycin (达托霉素)
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norvancomycin 去甲万古霉素 ; teicoplanin 替考 拉宁 ≈vancomycin with lower toxicity
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Daptomycin 达托霉素
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daptomycin Eli Lilly; Cubist company Novel cyclic lipopeptide antibiotic 环脂肽抗生素 Strong activity against Gram-positive organisms, even multi-resistant bacteria
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Fosfomycin 磷霉素
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Fosfomycin Wide spectrum; low toxicity; no cross- resistance and allergy Inhibiting bacterial cell wall biogenesis (enzyme inhibitor)
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Further reading Fischbach MA, Walsh CT. Antibiotics for emerging pathogens. Science. 2009 Aug 28;325(5944):1089-93.
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