β-lactam antibiotics (β- 内酰胺类抗生素）

Penicillin nucleus. β- lactam is the square at the center.

二十世纪十大分子 : aspirin : isooctane （异辛烷，与汽车工业有关） : penicillin G : 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 ） : nylon 6,6 ( 用于二战，代替丝织物 ) : DNA : progestin （黄体激素， contraceptives ） : DDT （对鸟、动物有害） : fluoxetine, introduced by Eli Lilly in 到 当时为止处方最多的抗抑郁药，在 90 多个国家应用。 : carbon nanotubes

Penicillins （青霉素类）

Natural penicillins Penicillin G Pharmacokinetics: destroyed easily by gastric acid distribution widely and 5% across BBB when in meningitis renal tubular excretion in prototype

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）

淋病奈瑟菌

放线菌

放线菌病

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.

Peptidoglycan （肽聚糖） is a 3D molecule Cross links are both horizontal and vertical between glycan chains stacked atop one another.

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

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, …)

Semi-synthetic penicillins Penicillin G Advantages disadvantages －－－－－－－－－－－－－－－－－－－－－－ high efficacyacid-irresistant low toxicity β-lactamase-irresistant cheapnarrow spectrum easy to use high allergic reactions －－－－－－－－－－－－－－－－－－－－－－

6-aminopenicillanic acid (6-APA, 6- 氨基青霉烷酸）

Semi-synthetic penicillins Penicillin V resists destruction by gastric juice (oral route OK) Still β-lactamase-irresistant Less efficient when penicillin G is effective

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

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

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

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

Cephalosporins （头孢菌素类）

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

7-aminocephalosporanic acid （ 7-ACA, 7- 氨基头孢烯酸）

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

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 !!!

Carbapenems （碳青霉烯类）

Other β-lactam penicillins Imipenem （亚胺培南）

imipenem

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

Meropenem （美罗培南） Dehydropeptidase- resistant Even wider antibacterial spectrum than imipenem

Cephamycins （头霉素类）

Cephamycins ≈second generation of cephalosporin Cefoxitin 头孢西丁； Cefmetazole （头孢美唑）

Oxacephems （氧头孢烯类）

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

Monocyclic β-lactam antibiotic 单环 β- 内酰胺抗生素

Monocyclic β-lactam antibiotic strong activity against susceptible gram- negative bacteria including Pseudomonas aeruginosa. like aminoglycosides, but no renal toxicity Aztreonam 氨曲南

β-lactamase inhibitors and compound preparation β- 内酰胺酶抑制剂及复方制剂

Clavulanic acid 克拉维酸

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

Glycopeptide antibiotics 糖肽类 and Other antibiotics

Vancomycin （万古霉素） Borneo 婆罗洲丛林土 壤 Eli Lilly, EC Kornfeld

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

Scanning electron micrographs of vancomycin- resistant Enterococcus

vancomycin Severe ototoxicity and nephrotoxicity, etc. being replaced by linezolid （利奈唑胺） and daptomycin （达托霉素）

norvancomycin 去甲万古霉素 ; teicoplanin 替考 拉宁 ≈vancomycin with lower toxicity

Daptomycin 达托霉素

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

Fosfomycin 磷霉素

Fosfomycin Wide spectrum; low toxicity; no cross- resistance and allergy Inhibiting bacterial cell wall biogenesis (enzyme inhibitor)

Further reading Fischbach MA, Walsh CT. Antibiotics for emerging pathogens. Science Aug 28;325(5944):