1. BlockⅤ: pharmacology Chemotherapeutic drugs (化学治疗药物)
汤慧芳
Tel:

2. (1)Chemotherapy(化学治疗, 简称化疗) (2)Chemotherapeutic drugs:
Antimicrobial drugs(抗微生物药);
Antiparasitic durgs(抗寄生虫药);
Antineoplastic drugs(抗肿瘤药).
(3)Antimicrobial drugs:
Antibacterial drugs(抗菌药);
Antifungal drugs(抗真菌药);
Antiviral drugs(抗病毒药).

3. Contents Part 1. General considerations of anti-microbial agents
Part 2. Bacterial cell wall synthesis inhibitors
Part 3. Bacterial protein synthesis inhibitors
Part 4. Synthetic antimicrobial agents
Part 5. Antifungal agents
Part 6. Antiviral agents
Part 7. Antituberculous drugs
Part 8. The drugs treated parasitic infections

4. Antimicrobial drugs classification
According to bioactivity
Anti G+ antibiotic
Anti G- antibiotic
Broad-spectrum antibiotic
Anti mycobacterium（分支杆菌） antibiotic
Anti anaerobe（厌氧菌） antibiotic
β- lactamase inhibitor

5. According to the chemical structure：
1、β-lactams: Penicillins; Cephalosporins;
2、Aminoglycosides;
3、Macrolides; Lincosamides ;Vancomycins
4、Tetracyclines; Chloramphenicol
5、Quinolones
6、Sulphonamides
7、Nitrofurans
8、Antimycobacterial agents
9、others: Oxazolidinones; Streptogramins

6. History of Antimicrobial Therapy
1909 Ehrlich discovers Salvarsan（撒尔佛散，治疗梅毒特效剂）
“Magic bullet” for treatment of syphilis（梅毒）
1928 Fleming discovers penicillin(青霉素)
1932 Domagk discovers sulfonamides（磺胺类药物）
1940s Penicillin and streptomycin （链霉素）used widely, cephalosporins （头孢菌素）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大环内酯类)
1956 Vancomycin （万古霉素）used for penicillin-resistant S. aureus
1957 Kanamycin（卡那霉素） discovered (aminoglycosides氨基苷类)
1962 Nalidixic acid （萘啶酸）discovered (quinolones喹诺酮类)
1980s Fluoroquinolones（氟喹诺酮类）, broad spectrum cephalosporins
2000s Newer agents to combat resistant pathogens
There is a very long history that people discovered many drugs to fight against microbes that cause diseases, but we haven’t got the final victory. Since, both microbes and cancer cells can evolve resistance to drug therapies.

7. 抗生素的发展史

11. General considerations of antimicrobial agents (抗微生物药物概论)
Part 1.
General considerations of antimicrobial agents
(抗微生物药物概论)

12. Contents 1. Overview 2. Term and definition
3. Classification and mechanism of antibacterial action
4. Bacterial resistance

13. Antimicrobial drugs: 1. Overview: Antibacterial drugs(抗菌药);
Antifungal drugs(抗真菌药);
Antiviral drugs(抗病毒药).

14. The relationship of the host, microorganisms, antimicrobial drugs.
Adverse effects
Resistance
Pharmacokinetics
Therapeutic Effects
pathogenicity
Interactions between drug , human body, and pathogens is complex.
Immunological
responses

15. Terminology 1. Antibacterial drugs(抗菌药) 2. Antibiotics(抗生素)
3. Bacteriostatic drugs(抑菌药)
4. Bactericidal drugs(杀菌药)
5. Antibacterial spectrum(抗菌谱)
6. Chemotherapetic index (化疗指数,CI)
7. Minimum inhibitory concentration (最小抑菌浓度, MIC)
8. Minimum bactericidal concentration (最小杀菌浓度, MBC)
9. Concentration Dependent killing
10. Post antibiotic effect (抗生素后效应,PAE)
11. Time-dependent killing
There are many terms to describe the antimicrobes properties.

16. 2. Terms and definition: (1)Antibacterial drugs(抗菌药):
Substances that can kill bacteria and/or inhibit its growth.
including:
①Antibiotics(抗生素);
②Synthetic antimicrobial agents, such as sulfonamides(磺胺类) and quinolones(喹诺酮类), etc.

17. Terms and definition
(2)Antibiotics(抗生素):
Substances produced by various species of microorganisms(bacteria, fungi, actinomyces, etc.), which can kill other microorganisms or inhibit their growth.

18. (3)Chemotherapetic index: LD50/ED50, or LD5/ED95
Terms and definition
(3)Chemotherapetic index:
LD50/ED50, or LD5/ED95
(4)Antibacterial spectrum(抗菌谱 );
(5)Bacteriostatic drugs(抑菌药);
(6)Bactericidal drugs(杀菌药);

19. Terms and definition
agents

20. (7)Minimum inhibitory concent-ration(MIC);
Terms and definition
(7)Minimum inhibitory concent-ration(MIC);
(8)Minimum bactericidal concen-tration(MBC):
MBC ≥ MIC;
if MBC > 32 times MIC  resistance.

21. 7. Minimum inhibitory concentration (MIC)
Antimicrobial Susceptibility Testing
7.Minimum inhibitory concentration (MIC)
The lowest concentration of an antimicrobial that will inhibit the visible growth of a microorganism after overnight incubation
Used by diagnostic laboratories mainly to confirm resistance, but most often as a research tool to determine the in vitro activity of new antimicrobials, and data from such studies have been used to determine MIC breakpoints.
8. Minimum bactericidal concentration (MBC)
The lowest concentration of antimicrobial that will prevent the growth of an organism after subculture on to antibiotic-free media.
MBC determinations are undertaken less frequently and their major use has been reserved for isolates from the blood of patients with endocarditis
7. Minimum inhibitory concentration (MIC)
8. Minimum bactericidal
concentration (MBC): 99.9% decrease in growth over 24 hours

22. Incubate 18 to
24 hr at 37℃
Measure
diameters of
nongrowth
zones
Disk diffusion method for testing bacteria for susceptibility to specific antimicrobial drugs.

23. Terms and definition
9. Concentration Dependent killing: situation in which the bactericidal activity of a drug depends by how much the drug concentration exceeds the Minimum inhibitory concentration of the organism in question. e.g. aminoglycosides and quinolones
10. Time-dependent killing: situation in which the bactericidal activity of a drug depends how long the drug concentration exceeds the Minimum inhibitory concentration of the organism in question. e.g. -lactams and vancomycin
11. Post antibiotic affect (PAE) : Persistence of suppression of bacterial growth after limited exposure to an antimicrobial agent. e.g. aminoglycosides
11. Post antibiotic effect (PAE)
Refers to a period of time after complete removal of an antibiotic during which there is no growth of the target organism
Several factors influence the presence or duration of the PAE including the type of organism, type of antimicrobial, concentration of antimicrobial, duration of antimicrobial exposure, and antimicrobial combinations.

24. Classification and mechanism of antibacterial action:
(1) inhibit synthesis of bacterial cell walls;
(2) act directly on the cell membrane of the microorganism and affect its permeability, and leading to leakage of intracellular compounds;
(3) inhibit protein synthesis;
(4) affect bacterial nucleic acid metabolism;
(5) The anti-metabolites of folic acid, that can block essential enzymes of folic acid synthetic metabolism.

25. Classification and mechanism of action① ④ ⑤ ③ ②

26. Classification and mechanism of action
(1)Inhibiting synthesis of bacterial cell walls:
UDP-乙酰胞壁酸-5肽
双糖十肽聚合物

27. Classification and mechanism of action
-Lactam antibiotics
vancomycin
transpeptidase

28. Classification and mechanism of action
(2)Affecting permeability of membrane:
①Ionic-adsorbed(streptomycin);
②binding to ergosterol(amphotercin B);
③Inhibiting the synthesis of ergosterol (imidazoles);
④Surface-active agent, that interact strongly with phospholipids(polymixins).

29. Classification and mechanism of action
(3)Inhibiting protein synthesis:
affecting the function of 30S：streptomycin, Tetracyclines(四环素类)
affecting the function of 50S：
streptomycin, Macrolides (大环内酯类), lincomycins, chloramphenicol etc.

30. Inhibiting protein synthesis
利奈唑胺
氨基苷类
氨基苷类
氨基苷类
四环素类
氯霉素类
大环内酯类
林可霉素类

31. Classification and mechanism of action
(4)Affecting bacterial nucleic acid metabolism: quinolones, etc.

32. Pteridine(蝶啶) + PABA(对氨苯甲酸) Blocked by sulfonamides
Classification and mechanism of action
(5)Blocking enzymes of folate metabolism:
Pteridine(蝶啶) + PABA(对氨苯甲酸)
Dihydropteroate
synthase
Blocked by sulfonamides
Dihydropteroic acid(二氢蝶酸)
Glutaminic acid
Dihydrofolic acid(二氢叶酸)
NADPH
Dihydrofolate
reductasease
Blocked by trimethoprim
NADP
Tetrahydrofolic acid(四氢叶酸)

33. Bacterial Resistance

34. 4. Bacterial resistance:
(1)Category of resistance:
①Intrinsic resistance:
Inherent features
usually expressed by chromosomal genes
②Acquired resistance:
emerge from previously sensitive bacterial populations
Caused by mutations in chromosomal genes
Or by acquisition of plasmids or transposons

35. (2)Mechanism of bacterial resistance:
①Enzymatic inactivation and modification;
②Inhance active efflux system:
③Decreased permeability;
④Target alteration;

36. Mechanism of bacterial resistance
①To produce inactivated enzyme: IM OM
Penicillin
b-lactam
Penicillinase
Inactive
Kanamycin
Acetylation
Phosphorylation
Adenylyation
1B. Enzymatic modification
e.g. Aminoglycoside modification
1A. Enzymatic inactivation
e.g. b-lactamase

37. Mechanism of bacterial resistance
② To enhance active efflux system(主动外排系统):

38. Mechanism of bacterial resistance
③ Decreased permeability :
Absence of, mutation in, or loss of the appropriate porins(膜孔蛋白) channel can slow the rate of drug entry into the cell, or prevent entry altogether, reducing the effective drug concentration at the target site.

39. Porin channel(膜孔蛋白通道)
Bacterial Resistance
Mechanism of bacterial resistance
Porin channel(膜孔蛋白通道)

40. Mechanism of bacterial resistance
④ Target alteration :
Mutation of the natural target(such as resistance to fluoroquinolone).
Target modification(ribosomal protection type of resistance to macrolides and tetracyclines).
Substitution with a resistant alternative to the natural, susceptible target (such as methicillin resistance in staphylococci).

41. ③Transformation(转化); ④Conjugation(接合).
Bacterial Resistance
The transfer of resistance genes:
①Mutations(突变);
②Transduction(转导);
③Transformation(转化);
④Conjugation(接合).

42. The transfer of resistance genes
Bacterial Resistance
The transfer of resistance genes
①Mutations(突变):
which may occur in the gene encoding.
1)The target protein;
2)The protein involved in drug transport;
3)Act on regulatory gene or promoter(启动子) affecting expression of the target, a transport protein, or an inactivating enzyme.
such as aminoglycosides, quinolones, etc.

43. The transfer of resistance genes
Bacterial Resistance
The transfer of resistance genes

44. Mutations May occur in the gene encoding i) The target protein
ii) A protein involved in drug transport
iii) A protein important for drug activation
iv) A regulatory gene or promoter
affecting expression of the target, a
transport protein, or an inactivating
enzyme.

45. The transfer of resistance genes
Bacterial Resistance
The transfer of resistance genes
②Transduction(转导):
acquisition of bacterial DNA from bacteriophage(噬菌体) that has incorporated DNA from a previous host bacterium within its outer protein coat.
Some phages can carry plasmids that code for penicillinase, or genes encod-ing resistance to erythromycin, tetracy-cline, or chioramphenicol.

46. Transduction
Transduction is acquisition of bacterial DNA from a bacteriophage (噬菌体）that has incorporated DNA from a previous host bacterium within its outer protein coat. Some phages can carry plasmids that code for penicillinase, or genes encoding resistance to erythromycin, tetracycline, or chloramphenicol.

47. The transfer of resistance genes
Bacterial Resistance
The transfer of resistance genes
③Transformation(转化):
Uptake and incorporation of DNA that is free in the environment into the host genome by homologous recombination.

48. The transfer of resistance genes
Bacterial Resistance
The transfer of resistance genes

49. The transfer of resistance genes
Bacterial Resistance
The transfer of resistance genes
④Conjugation(接合):
The passage of genes from cell to cell by direct contact through a sex pilus(性菌毛) or bridge(桥接).

50. Transformation Conjugation Bacterial Resistance
Transformation Uptake and incorporation of DNA that is free in the environment into the host genome by homolgous recombination.
Conjugation
The passage of genes from cell to cell by direct contact through a sex pilus or bridge is termed conjugation.

52. Multi-drug resistance MDR (了解)
耐甲氧西林金葡菌MRSA
社区获得性耐甲氧西林金葡菌（community-associated。CA—MRSA）
医院获得性耐甲氧西林金葡菌（ Hospital-associated ，HA-MRSA
Methicillin-resistant coagulase negative staphylococci, MRCNS
PBP-2a
3.Penicillin-resistant streptococcus pneumoniae, PRSP
PBP-1a, PBP-2a, PBP-2x, PBP-2b
Active efflux system
4.Vancomycin-resistant Enterococcus, VRE
van-A, van-B, van C-1, van C-2, van C-3, van D, van E

53. Multi-drug resistance MDR (略)
5. The 3rd generation-cephalosporins -resistant
Extended spectrumβ-lactamases, ESBL
Class I chromosone mediated β-lactamases
6.Carbapenem -resistant
OprD porin
7.Quinolone-resistant escherichia coli, AREC
Active efflux system

54. Let’s take a rest !

55. Beta-Lactam & Other Cell Wall-& Membrane- Active Antibiotics
Part 2.
Beta-Lactam & Other Cell Wall-& Membrane- Active Antibiotics

56. Beta-Lactam & Other Cell Wall- & Membrane- Active Antibiotics

57. Classification of -Lactam Antibiotics
Ⅰ. Penicillins(青霉素类)
Ⅱ. Cepharosporins(头孢菌素类)
Ⅲ. Other -lactam antibiotics:
1. Cephamycins(头霉素类)
2. Carbapenems(碳青霉烯类)
3. Monobectams(单环类)
4. Oxacephalosporins(氧头孢烯类)
Ⅳ. -lactamase inhibitors(内酰胺酶抑制剂)

58. Core structures of beta-lactam antibiotic families
(青霉素类)
Core structures of beta-lactam antibiotic families
(头孢菌素类)

59. Beta-Lactam antibiotics

60. (单环类)
(碳青霉烯类)
(亚胺培南——碳青霉烯类)

61. Chemical structure of penicillins
A. Nature Penicillins:
(酰基侧链)
(噻唑烷环)
(青霉素类)
(-内酰胺环)
Chemical structure of penicillins

62. Penicillins 1. Classification of Penicillins: (1)Nature penicillins:
Penicillin G(苄青霉素, 简称青霉素)
(2)Penicillinase-resistant penicillins:
Oxacillin(苯唑西林)
(3)Broad-spectrum penicillins:
Amoxicillin(阿莫西林)
(4)Anti-pseudomonas penicillins:
Ticarcillin(替卡西林)
(5)Anti-G- bacilli penicillins:
Mecillinam(美西林)

63. Penicillins 2. Antimicrobial activity:
The penicillin-susceptible bacteria:
(1)G+ bacilli(革兰阳性杆菌);
(2)Non-penicillinase-producing strains of most G- cocci(大多数不产青霉素酶的球菌) and Nisseria(奈瑟菌属), etc.
such as: Meningococcus(脑膜炎球菌), Gonococcus(淋球菌), etc.
(3)Spirochetes(螺旋体), etc.

64. Penicillins 3. Mechanism of action:
(1)Inhibiting transpeptidase(转肽酶, PBP, 青霉素结合蛋白), and inhibiting the synthesis of bacterial cell walls.
(2)Activation of cell-wall autolytic enzy-me(自溶酶).

65. Comparison of the structure and composition of G+/ G- cell walls.
Penicillins
Comparison of the structure and composition of G+/ G- cell walls.

66. Penicillins Penicillins
Penicillins & cephalosporins can inhibit the transpeptidase reaction in sen-sitive organism (敏感菌).
Penicillins

67. 4. Mechanism of resistance:

68. Penicillins (1)to produce penicillinase(-lactamase) by bacteria
(青霉素酶)
(酰胺酶)
(青霉素裂解酸)
(6-氨基青霉烷酸)

69. Penicillin -Mechanism of resistance

70. Penicillins (2)to alter PBP, decreased affinity for the antibiotic;
(3)to make deficiency of porins, or enhance active efflux system,
let penicillins does not reach its target, and inability to be effective.
(4) Lack of the autolysins

71. Antibiotic efflux pumps of G- bacteria.
Penicillins
Antibiotic efflux pumps of G- bacteria.

72. Penicillins 5. Clinical Uses: (1)Streptococcal(链球菌) infections:
such as:
Pharyngitis(咽炎), Scarlet fever(猩红热);
Rheumatic fever(风湿热), Pneumonia(肺炎), Endocarditis(心内膜炎), etc.
(2)Nisseria (奈瑟菌) infections:
Meningitis(脑膜炎);
Gonorrhea(淋病), etc.

73. Penicillins (3)Leptospira(螺旋体) infection:
such as: Liptospirosis(钩端螺旋体病), Syphilis(梅毒), Recurrent fever(回归热).
(4)G+ bacilli(G+ 杆菌) infection:
such as: Diphtheria(白喉), Tetanus(破伤风), Anthrax(炭疽病), etc.
(5)Staphylococcal(葡萄球菌) infection
(generally resistant to penicillin G).

74. Penicillins 6. Adverse effects:
Penicillins are among the safest of antibiotics, produce few direct toxic reactions,
the most of the serious side effects are hypersensitivity reactions.

75. Penicillins (1)Hypersensitivity reactions:
Itching(痒), rashes, fever, serum sick-ness, angioneurotic oedema(血管神经性水肿).
Anaphylactic shock (5/10 000).
(2)Other adverse reactions:
Phlebitis(静脉炎), when i.v.;
Local inflammatory reactions, in injection site when i.m.;
Jarisch-Herxheimer reaction(赫氏反应) when treatment of syphilis, liptospirosis.

76. Penicillins 7. ADME of Penicillin G: Be destroyed easily by p.o.
Administration by i.m. or i.v. gtt.
widely distributed (even in CSF, when menings is infective);
Eliminated in the urine.

77. Penicillins 8. Preparation of long-acting penicillin G:
Benzathine penicillin G(苄星青霉素)
Procain penicillin(普鲁卡因青霉素)

78. Phenoxymethylpenicillin (苯氧甲基青霉素, Penicillin V)
B. Semi-synthetic Penicillins:
1. Penicillins by oral administration（耐酸青霉素）:
Phenoxymethylpenicillin
(苯氧甲基青霉素, Penicillin V)
It is resistant to gastric acid, and be well absorbed(60%) when it is given on an empty stomach.
Its half-life(t½) is longer than that of penicillin G.
A satisfactory substitute for Penicillin G to treat tonsilitis(扁桃体炎), or Pharyn-gitis(咽炎), etc.

79. Semisynthetic Penicillins
2. The penicillinase-resistant penicillins(耐酶青霉素):
Oxacillin(苯唑西林),
Cloxacillin(氯唑西林),
Dicloxacillin(双氯西林)
It is stable in an acidic medium, can be administrated by po, or im, iv ; and it is resistant to cleavage by penicillinase.
It is used for treatment of penicillin G-resistance staphylococcal infection.

80. Semisynthetic Penicillins Piperacillin(哌拉西林), etc.
3. Broad spectrum penicillins（广谱青霉素）:
Amipicillin(氨苄西林),
Carbenicillin(羧苄西林),
Piperacillin(哌拉西林), etc.
They have similar antibacterial activity and a broader spectrum.
All can be destroyed by -lactamase.

81. Broad spectrum penicillins
Semisynthetic Penicillins
(1)Ampicillin(氨苄西林), Amoxicillin(阿莫西林)
Pseudomonas aeruginosa(铜绿假单孢菌
——绿脓杆菌)-resistance.
Clinical Uses:
Upper respiratory infections; Urinary tract infections; Meningitis; Salmonella infections.
(2)Carbenicillin(羧苄西林),Ticarcillin(替卡西林)
With activity against Pseudomonas aeruginosa and some Proteus(变形杆菌).

82. Broad spectrum Penicillins
Semisynthetic Penicillins
(3)Piperacillin(哌拉西林),Mezlocillin(美洛西林)
They have the broadest antibacterial spectrum, and the most activity of the penicillins, with activity against Pseudo-monas aeruginosa, etc.
Clinical Uses:
For the treatment of the patients with severe infection caused by G- bacteria, us-ually in combination with aminoglycoside (氨基苷类).

83. 4. Anti-G- bacilli penicillins:
Semisynthetic Penicillins
Mecillinam(美西林),
Temocillin(替莫西林)
Bacteriostatic drugs
Narrow antibacterial spectrum: have activity against some G- bacilli.

84. Ⅱ. Cepharosporins (头孢菌素类)

86. （头孢孟多）
（头孢西丁）

87. Therapeutic advantages of some clinically useful cephalosporins.

88. B. Classification and Features:
Cepharosporins
1. First generation:
Cefazolin(头孢唑林), Cefradine(头孢拉定), Cefalexin(头孢氨苄), etc.
(1)more active than second and third genera-tion against certain G+ microoganisms;
(2)more impervious than second and third ge-neration to attack by staphyloccal -lactamase;
(3)less active than second and third genera-tion against certain G- microoganisms;
(4)non-stable to G- bacilli -lactamase;
(5)more activity against certain Pseudomonas (铜绿假单孢菌), anaerobes(厌氧菌), etc;
(6)certain kinds have kidney toxicity.

89. Cepharosporins 2. Second generation:
Cefuroxime(头孢呋辛), Cefamandole(头孢孟多), Cefaclor(头孢克洛), etc.
(1)more active than first generation against certain G- bacilli and more impervious than first generation G- bacilli -lactamase;
(2)somewhat less active than first generation against G+ cocci but more than third generation;
(3)active against anaerobes(厌氧菌);
(4)lack activity against Pseudomonas;
(5)less toxic than first generation to kidney.

90. Cepharosporins 3. Third generation:
Ceftazidime(头孢他啶), Ceftriaxone(头孢曲松), etc.
(1)far more active than first and second gene-ration against G- bacilli;
(2)be highly resistant to -lactamase produced by G- bacilli;
(3)with the extended spectrum against anae-robes and Pseudomonas;
(4)well absorbed, penetration into tissue, blo-od and body cavity as well in sufficient concen-tration;
(5)less active than first and second generation against G+ cocci;
(6)less toxic to kidney.

91. （头孢哌酮）
（头孢噻肟）

92. Cepharosporins 4. Fourth generation:
Cefepime(头孢匹肟), Cefpirome(头孢匹罗), etc.
(1)resistant to type 1 -lactamase;
(2)more active than third generation against Enterbacter(耐肠杆菌);
(3)less active than third generation against Pseudomonas.

94. summary

95. 1st st st st
抗菌谱 G 强 G-
酶稳定性 好
肾毒性 大
半衰期 长
血脑屏障通透性 好

96. Ⅲ. Other -lactam antibiotics
1. Cephamycins(头霉素类):
Cefoxitin (头孢西丁)
It has the similar antibacterial activity and spectrum to the second generation cepharosporins,
also can be used for the treatment of anaerobic infections.

97. Other -lactam antibiotics
2. Carbapenems(碳青霉烯类):
Imipenem(亚胺培南)
Meropenem(美罗培南)
Panipenem (帕尼培南)
Ertapenem（厄他培南）
Broad spectrum: wide activity against gram-positive cocci (including some penicillin-resistant pneumococci), gram-negative rods, and anaerobes.
With the exception of ertapenem, the carbapenems are active against P aeruginosa and Acinetobacter species.

98. 抗生素的发展史

99. Imipenem+cilastatin(西司他丁)—Tienam(泰能), a drug that inhibits the degradation of imipenem by a renal tubular dipeptidase.
Panipenem+betamipron (倍他米隆)-Carbenin(克倍宁)

100. Other -lactam antibiotics
3. Monobectams(单环类):
Aztreonam(氨曲南)
Carumonam(卡芦莫南)
For the treatment of aerobic G+ bacilli infections.
Narrow-spectrum antibiotic.

101. 抗生素的发展史

102. Other -lactam antibiotics
4. Oxacephalosporins(氧头孢烯类)
Latamoxef(拉氧头孢)
Flomoxef(氟氧头孢)
Broad-spectrum antibiotic(anaerobic infections).

103. Ⅳ. -lactamase inhibitors (-内酰胺酶抑制剂)
Clavulanic acid(克拉维酸)
Sulbactam(舒巴坦)
Tazobactam(三唑巴坦)
Binding to -lactamases and inactivate them, thus preventing the destruction of -lactam antibiotics which are substrates for -lactamases.
They are most active against plasmid-encoded beta-lactamases such as those produced by gonococci, streptococci, E coli, and H influenzae. They are not good inhibitors of inducible chromosomal betalactamases formed by Enterobacter, Pseudomonas, and Serratia.

104. Penicillin -Mechanism of resistance

105. amoxicillin+ clavulanic acid = augmentin (奥格门汀)
The in vitro growth of Escherichia coli in the presence of amoxicillin, with and without clavulanic acid.
amoxicillin+ clavulanic acid = augmentin (奥格门汀)

106. 阿莫西林+ 克拉维酸 = 奥格门汀augmentin
氨苄西林+舒巴坦 = 优立新unasyn
替卡西林+克拉维酸 =替门汀/特美汀 timentin

107. OTHER CELL WALL OR MEMBRANE-ACTIVE AGENTS
Vancomycin
OTHER CELL WALL OR MEMBRANE-ACTIVE AGENTS
I. glycopeptide antibiotic（糖肽类）
Vancomycin (万古霉素)
& Teicoplanin（替考拉宁）

108. Vancomycin (万古霉素) Mechanism of action--Inhibit cell wall synthesis
-Lactam antibiotics
vancomycin
transpeptidase

109. Vancomycin(万古霉素) Vancomycin Antimicrobial spectrum: Pharmacokinetics
Narrow spectrum, active only against gram-positive bacteria, paticularly staphylococci
Pharmacokinetics
Poorly absorbed from intestinal tract, iv
Excreted from glomerular filtration 90%

110. Vancomycin
Vancomycin(万古霉素)
Clinical uses
Infection caused by MRSA, MRSE and penicillin-resistant pneumococcus
Treatment of antibiotic-associated enterocolitis caused by clostridium difficile po
Adverse reaction
Ototoxicity & nephrotoxicity
Red-man syndrome

111. Vancomycin
Teicoplanin(替考拉宁)
Similar to vancomycin in mechanism and antimicrobial spectrum
Can be given im as well as iv
Less adverse reactions

112. II. lipopeptide antibiotic(环脂肽类)
Daptomycin
II. lipopeptide antibiotic(环脂肽类)
Daptomycin(达托霉素)
Mechanism of action
Disruption of the bacterial membrane through the formation of transmembrane channels, resulting in a loss of membrane potential leading to inhibition of protein, DNA and RNA synthesis, which results in bacterial cell death.
Daptomycin is a novel cyclic lipopeptide with spectrum similar to vancomycin but active against vancomycin-resistant strains of enterococci and staphylococci.
The drug is eliminated via the kidney. Creatine phosphokinase should be monitored since daptomycin may cause myopathy.
daptomycin is inactivated by pulmonary surfactants; thus, it should never be used in the treatment of pneumonia.
Gram-positive activity; used in endocarditis and sepsis

113. Antimicrobial spectrum:
Daptomycin
Antimicrobial spectrum:
Daptomycin is unable to permeate the outer membrane of Gram-negative bacteria, thus its spectrum is limited to Gram-positive organisms only.
Daptomycin has activity against Staphylococci (including MRSA, VISA, and VRSA), Enterococci (both E. faecalis and E.faecium, including VRE), and Streptococci (including DRSP), as well as most other aerobic and anaerobic Gram-positive bacteria.

115. 抗生素的发展史

116. III. lipoglycopeptide antibiotic (脂糖肽类)
Telavancin (达巴万星)
It is an alternative to vancomycin, daptomycin, linezolid, and quinupristin/dalfopristin in treating complicated skin and skin structure infections, caused by resistant gram-positive organisms, including MRSA.
Mechanism of action：
Like vancomycin,inhibits bacterial cell wall synthesis. Unlike vancomycin, telavancin exhibits an additional mechanism of action similar to that of daptomycin, that involves disruption of the bacterial cell membrane, due to the presence of a lipophilic side chain moiety.

117. Adverse Effects
The most common adverse reactions ：taste disturbances, nausea, vomiting, insomnia, and foamy urine.
Telavancin is not recommended during pregnancy due to adverse developmental outcomes observed with animal data.
Prolong the QTc interval, use should be avoided in patients with a history of QTc prolongation, uncompensated heart failure, severe left ventricular hypertrophy, or patients receiving other medications that may prolong the QTc interval.
Telavancin may also interfere with tests used to monitor coagulation (PT/INR, aPTT, ACT, coagulation based Xa tests). Thus, blood samples monitoring coagulation should be collected as close to the next dose of telavancin as possible.

118. END OF CLASS