1. ß -lactam antibiotics Liming Zhou Department of pharmacology

2. Classification of drug Classification of drug The mechanism of antibacterial action The mechanism of antibacterial action Bacteria Resistance Bacteria Resistance

3. ß -lactam antibiotics in this chapter are classified into three sub-class. I. The penicillins I. The penicillins II. Cephalosporins II. Cephalosporins III. Other β-lactams III. Other β-lactams

4. I. The penicillins A. natural penicillins: Penicillin G and penicillin V A. natural penicillins: Penicillin G and penicillin V B. Semisynthetic penicillins. B. Semisynthetic penicillins.

5. II. Cephalosporins A. First generation cephalosporins A. First generation cephalosporins B. Second generation cephalosporins B. Second generation cephalosporins C. Third generation cephalosporins C. Third generation cephalosporins D.The fourth generation cephalosporins D.The fourth generation cephalosporins

6. III. Other β-lactams A. Cephamycins A. Cephamycins B. Carbapenems B. Carbapenems C. Monobactams C. Monobactams D. Oxacephems D. Oxacephems E.β-lactamase inhibitor E.β-lactamase inhibitor

7. The mechanism of antibacterial action The peptidoglycan is composed of glycan chains of N-acetyglucosamine and N-acetylmuramic acid. The peptidoglycan is composed of glycan chains of N-acetyglucosamine and N-acetylmuramic acid. The biosynthesis of peptidoglycan can be considered in three stages which the last one involves the completion of the cross-link. The biosynthesis of peptidoglycan can be considered in three stages which the last one involves the completion of the cross-link. This is accomplished by a tranpeptidation reaction, which involves transpetidase. This is accomplished by a tranpeptidation reaction, which involves transpetidase. The ß -lactam antibiotics combine with and inactivate the tranpeptidase. The ß -lactam antibiotics combine with and inactivate the tranpeptidase.

9. The mechanism of antibacterial action

10. The tranpeptidase is inactivated by ß -lactam antibiotics, they are the targets of β-lactam antibiotics and are named penicillin-binding protein (PBPs). The tranpeptidase is inactivated by ß -lactam antibiotics, they are the targets of β-lactam antibiotics and are named penicillin-binding protein (PBPs). The PBPs vary in their affinities for different ß -lactam antibiotics and several kinds of PBPs have confirmed. The PBPs vary in their affinities for different ß -lactam antibiotics and several kinds of PBPs have confirmed.

12. Bacteria Resistance In generally, there are three main mechanism of ß-lactam antibiotics resistance. (1) Nearly all bacteria can produce β- lactamase after contact with β-lactam antibiotics. β-lactamase can inactivate ß- lactam antibiotics through rupture the ß- lactam ring. Different microorganisms produce a number of distinct β-lactamase. (1) Nearly all bacteria can produce β- lactamase after contact with β-lactam antibiotics. β-lactamase can inactivate ß- lactam antibiotics through rupture the ß- lactam ring. Different microorganisms produce a number of distinct β-lactamase.

13. Bacteria Resistance (2) Many bacterial can alter PBPs with decreased affinity for ß-lactam antibiotics. This can result in failure of antibiotics binding to active sites. (2) Many bacterial can alter PBPs with decreased affinity for ß-lactam antibiotics. This can result in failure of antibiotics binding to active sites. (3) The concentration of antibiotics in target site is too low because of lacking of porin protein, such us OmpF and OmpC. This permeability block is particularly seen in resistance gram-negative bacteria that possess a complex outer layer. Increased active antibiotics efflux which reduce the drug in bacteria is the other reason for low concentration in target site (3) The concentration of antibiotics in target site is too low because of lacking of porin protein, such us OmpF and OmpC. This permeability block is particularly seen in resistance gram-negative bacteria that possess a complex outer layer. Increased active antibiotics efflux which reduce the drug in bacteria is the other reason for low concentration in target site

14. Penicillins I. Natural penicillins I. Natural penicillins Benzylpenicillin (Penicillin G) Benzylpenicillin (Penicillin G) It is the one of the natural penicillins used clinically and instable in water solution, gastric juice at pH 2. It is the one of the natural penicillins used clinically and instable in water solution, gastric juice at pH 2.

15. Structure

16. Antibacterial action Penicillin has great antibacterial activity to a variety of sensitive bacteria. Penicillin has great antibacterial activity to a variety of sensitive bacteria. The antibacterial spectrum includes: The antibacterial spectrum includes: Gram-positive cocci: Streptococcus pyogenes (group A, B, C, G, F), non-β-lactamase producing staphylococcus aureus, sensitive streptococcus pneumoniae, aerobic Gram positive cocci. Gram-positive cocci: Streptococcus pyogenes (group A, B, C, G, F), non-β-lactamase producing staphylococcus aureus, sensitive streptococcus pneumoniae, aerobic Gram positive cocci. Gram-positive bacilli: corynebacterium diphtheriae; bacillus anthracis; anaerobic clostridium tetani; clostridium perfringens; clostridium botulinum; actinomyces. Gram-positive bacilli: corynebacterium diphtheriae; bacillus anthracis; anaerobic clostridium tetani; clostridium perfringens; clostridium botulinum; actinomyces.

17. Antibacterial action Gram-negative cocci: nesseria meningitides; neisseria gonorrhoeae. Gram-negative cocci: nesseria meningitides; neisseria gonorrhoeae. Spirochetes: Treponema pallidum; leptospira spp.; borrelia burgdorferi. Spirochetes: Treponema pallidum; leptospira spp.; borrelia burgdorferi.

18. Pharmacokinetics When oral administrated, penicillin G is rapidly destroyed by gastric acid and has poor absorption. Often it is used by i.m or i.v. When oral administrated, penicillin G is rapidly destroyed by gastric acid and has poor absorption. Often it is used by i.m or i.v. The peak concentration time in blood is about 0.5 h, and it is nearly completely eliminated mainly by the kidney in 6 h when penicillin G is administrated by i.m. The peak concentration time in blood is about 0.5 h, and it is nearly completely eliminated mainly by the kidney in 6 h when penicillin G is administrated by i.m. The half-life is about 0.5 h. It has broad distribution, but cannot pass the blood-brain barrier, cannot reach the aqueous humor and succus prostaticus. The half-life is about 0.5 h. It has broad distribution, but cannot pass the blood-brain barrier, cannot reach the aqueous humor and succus prostaticus. When having cerebra inflammation, it can pass the damaged blood-brain barrier into cerebrospinal fluid. When having cerebra inflammation, it can pass the damaged blood-brain barrier into cerebrospinal fluid.

19. Clinical uses 1. Infection of streptococcus: S. pyogenes group A can caused pharyngitis （咽炎）, scarlatina （猩红热）, cellulitis （蜂窝织 炎）, suppurative arthritis, pneumonia, puerperal （分娩的） fever and blood poisoning. S. pyogenes group B, S. pneumoniae, S. viridans and S. faecalis can caused respiratory infection, meningitis, endocarditis, and blood poisoning. 1. Infection of streptococcus: S. pyogenes group A can caused pharyngitis （咽炎）, scarlatina （猩红热）, cellulitis （蜂窝织 炎）, suppurative arthritis, pneumonia, puerperal （分娩的） fever and blood poisoning. S. pyogenes group B, S. pneumoniae, S. viridans and S. faecalis can caused respiratory infection, meningitis, endocarditis, and blood poisoning.

20. Clinical uses 2.Pneumococcal infections: pneumococcal pneumonia, pneumococcal meningitis 2.Pneumococcal infections: pneumococcal pneumonia, pneumococcal meningitis 3.Treatment of meningococcal meningitis. 3.Treatment of meningococcal meningitis. 4.Treatment of gonococcal infections such as gonococcal urethritis, gonococcal arthritis and gonococcemia. 4.Treatment of gonococcal infections such as gonococcal urethritis, gonococcal arthritis and gonococcemia.

21. Clinical uses 5.Spirochete infection: Leptospirosis, lues and recurrent fever. 5.Spirochete infection: Leptospirosis, lues and recurrent fever. 6.Gram-positive bacilli infection: lockjaw （破 伤风）, diphtheria （白喉） and anthrax （炭 疽）. 6.Gram-positive bacilli infection: lockjaw （破 伤风）, diphtheria （白喉） and anthrax （炭 疽）. 7.Infections with sensitive anaerobes 7.Infections with sensitive anaerobes

22. Adverse reactions The toxicity of penicillins is very low. Allergic reactions: drug rash, dermatitis, serum sickness, anaphylactic shock and hemolytic anemia. Allergic reactions: drug rash, dermatitis, serum sickness, anaphylactic shock and hemolytic anemia. Before using this kind of drugs, the medical institution must prepare drugs for treatment of anaphylactic shock. Before using this kind of drugs, the medical institution must prepare drugs for treatment of anaphylactic shock.

23. Adverse reactions Jarisch-Herxheimer reaction: after penicillin treatment of spirochete infection, some patients show symptoms of ague, fever, laryngeal pain, headache and tachycardia. It is sometimes life threaten. This reaction is due to the large number of kill spirochete, so the dose at the beginning should not be high. Jarisch-Herxheimer reaction: after penicillin treatment of spirochete infection, some patients show symptoms of ague, fever, laryngeal pain, headache and tachycardia. It is sometimes life threaten. This reaction is due to the large number of kill spirochete, so the dose at the beginning should not be high.

24. Semisynthetic penicillins Oral administration (acid stable) β-lactamase non-stable penicillins Penicillin V (phenoxymethylpenicillin). Penicillin V (phenoxymethylpenicillin). Antibacterial action: This kind of penicillins is similar with penicillin G with the same antibacterial spectrum but lower activity. Antibacterial action: This kind of penicillins is similar with penicillin G with the same antibacterial spectrum but lower activity.

25. Semisynthetic penicillins Clinical uses: It is used in slight infection caused by gram-posotive cocci such as pharyngitis, amygdalitis( 扁桃体炎 ) and prophylactic use for rheumatic fever. Clinical uses: It is used in slight infection caused by gram-posotive cocci such as pharyngitis, amygdalitis( 扁桃体炎 ) and prophylactic use for rheumatic fever. Adverse reaction: it can cause allergic reaction (most slight reaction) and gastrointestinal reaction (burning sensation, nausea, vomiting and diarrhea) Adverse reaction: it can cause allergic reaction (most slight reaction) and gastrointestinal reaction (burning sensation, nausea, vomiting and diarrhea)

26. B Penicillinase-resistant penicillins Methicillin; Dicloxacillin; Cloxacillin and Oxacillin belong to this kind of penicillins. Methicillin; Dicloxacillin; Cloxacillin and Oxacillin belong to this kind of penicillins. Only methicillin is not stable in acid and the other can administer orally. Only methicillin is not stable in acid and the other can administer orally. Antibacterial activity: it has powerful activity on penicillinase producing S. aureus, less activity on streptococcus, and resistance to gram-negative bacteria. Antibacterial activity: it has powerful activity on penicillinase producing S. aureus, less activity on streptococcus, and resistance to gram-negative bacteria.

27. B Penicillinase-resistant penicillins Clinic uses: Clinic uses: These antibiotics also have many resistant bacteria now. These antibiotics also have many resistant bacteria now. The dicloxacillin has the lowest resistant bacteria at present. The dicloxacillin has the lowest resistant bacteria at present. MRSA: Methicillin of resistance to S. aureus MRSA: Methicillin of resistance to S. aureus

28. C Broad spectrum penicillins This kind of penicillins include ampicillin, amoxicillin. This kind of penicillins include ampicillin, amoxicillin. Antibacterial activity: ampicillin and have amoxicillin similar action to penicillin G sensitive bacteria. Antibacterial activity to gram-negative bacteria for these penicillins is greater than that for Penicillin G. Antibacterial activity: ampicillin and have amoxicillin similar action to penicillin G sensitive bacteria. Antibacterial activity to gram-negative bacteria for these penicillins is greater than that for Penicillin G.

29. C Broad spectrum penicillins Pharmacokinetics: The absorption of ampicillin and amoxicillin is about 30% and 90% respectively. The absorption of ampicillin and amoxicillin is about 30% and 90% respectively. When inflammation occurring, effective concentration of these drugs can obtained in tympanitis effusion, bronchia secretion, ascitic fluid, articular cavity effusion and cerebrospinal fluid. When inflammation occurring, effective concentration of these drugs can obtained in tympanitis effusion, bronchia secretion, ascitic fluid, articular cavity effusion and cerebrospinal fluid.

30. D Penicillins of treatment for Pseud. aeruginosa infection D Penicillins of treatment for Pseud. aeruginosa infection These drugs include Carbenicillin and piperacillin Antibacterial activity: The antibacterial spectrum of these drugs is effective for pseud. aeruginosa and bacillus proteus. Antibacterial activity: The antibacterial spectrum of these drugs is effective for pseud. aeruginosa and bacillus proteus. Therapeutic uses: It is usually used to infection of Pseud. aeruginosa and ß - lactamase producing bacteria that resistant to ampicillin. Therapeutic uses: It is usually used to infection of Pseud. aeruginosa and ß - lactamase producing bacteria that resistant to ampicillin.

31. E Penicillins of treatment for Gram- negative bacilli infection These drugs include mecillinam and temocillin Antibacterial activity: The antibacterial spectrum of these drugs is effective for Gram-negative bacilli infection, Antibacterial activity: The antibacterial spectrum of these drugs is effective for Gram-negative bacilli infection, Therapeutic uses: These penicillins can be used in urinary tract infection. Therapeutic uses: These penicillins can be used in urinary tract infection.

32. Cephalosporins Cephalosporins are the semisynthetic antibiotics derived from 7-Amino cephalosporanic acid (7- ACA) — the cephem nucleus of cephalosporins. Cephalosporins are the semisynthetic antibiotics derived from 7-Amino cephalosporanic acid (7- ACA) — the cephem nucleus of cephalosporins. They are similar to penicillins in terms of mechanism of action, chemical structure, and toxicities They are similar to penicillins in terms of mechanism of action, chemical structure, and toxicities

33. First generation cephalosporins First generation cephalosporins Cefazolin; Cefadroxil; Cefalexin; Cefalothin; Cefapirin; cefradine. Cefazolin; Cefadroxil; Cefalexin; Cefalothin; Cefapirin; cefradine.

34. First generation cephalosporins Pharmocological properties Pharmocological properties It exhibits good activity against gram-positive bacteria, but less activity against gram negative organisms: (a) greater activity to gram-positive bacteria than the second and third generation, (a) greater activity to gram-positive bacteria than the second and third generation, (b) Less stable than second and third generation to β- lactamase, (b) Less stable than second and third generation to β- lactamase, (c) Less activity than second and much less activity than third generation to gram-negative bacilli; (c) Less activity than second and much less activity than third generation to gram-negative bacilli; (d) some drugs have kidney toxicity. (d) some drugs have kidney toxicity.

35. First generation cephalosporins Clinical uses These antibiotics are often used to treat gram- positive bacteria infection. These antibiotics are often used to treat gram- positive bacteria infection. Injecting route drugs are used for moderate infection caused by aerobic bacteria and some severe infection by sensitive bacteria. Injecting route drugs are used for moderate infection caused by aerobic bacteria and some severe infection by sensitive bacteria.

36. Second generation cephalosporins: Second generation cephalosporins: Cefuroxime, cefamandole, cefaclor ceforanide Cefuroxime, cefamandole, cefaclor ceforanide

37. Second generation cephalosporins Pharmocological properties Second-generation drugs exhibit enhanced activity against gram-negative bacteria, but much less enhancement compared to third generation agents: Second-generation drugs exhibit enhanced activity against gram-negative bacteria, but much less enhancement compared to third generation agents: (a) better anti-bacteria activity to gram-negative than first generation cephalosporins, but less than do third generation drugs, (b) (b) more stability to β-lactamase than first generation cephalosporins, (c) (c) less kidney toxicity than first generation.

38. Second generation cephalosporins Clinical uses It is the first choice drugs for gram-negative bacteria infectious diseases, and the other indications are similar with first generation cephalosporins. It is the first choice drugs for gram-negative bacteria infectious diseases, and the other indications are similar with first generation cephalosporins.

39. Third generation cephalosporins Third generation cephalosporins Cefotaxime, ceftazidime, ceftriaxone, cefoperazone, ceftizoxime, cefixime,cefodizime Cefotaxime, ceftazidime, ceftriaxone, cefoperazone, ceftizoxime, cefixime,cefodizime

40. Third generation cephalosporins Pharmocological properties Third-generation drugs exhibit the lest activity against gram- positive bacteria, but most potent activity against gram- negative bacteria : (a) extended antibacterial spectrum, include Pseud. aeruginosa; (b) less activity on gram-positive bacteria than first and second generation; (c) most active on gram-negative bacteria; (d) high stability with β-lactamase; (e) easy penetrate to different tissues, and then have broad distribution; (f) little kidney toxicity.

41. Third generation cephalosporins Clinical uses These drugs are used for severe gram-negative resistant bacilli infection. These drugs are used for severe gram-negative resistant bacilli infection. And also used for complex infection. And also used for complex infection.

42. The fourth generation cephalosporins The fourth generation cephalosporins Cefepime and cefpirome have similar antibacterial activity with third generation on most gram-negative bacilli, but more stable to β-lactamase. Cefepime and cefpirome have similar antibacterial activity with third generation on most gram-negative bacilli, but more stable to β-lactamase.

43. Other β-lactams Cephamycins Natural product is cephamycin and the semisynthetic cefoxitin is in clinical use. Natural product is cephamycin and the semisynthetic cefoxitin is in clinical use. It has similar antibacterial activity with second- generation cephalosporins, and good activity to anaerobe. It is used for mixed infection of aerobe and anaerobe. It has similar antibacterial activity with second- generation cephalosporins, and good activity to anaerobe. It is used for mixed infection of aerobe and anaerobe.

44. Other β-lactams Carbapenems Carbapenems Carbapenems includes Imipenem, meropenem and panipenem. Carbapenems includes Imipenem, meropenem and panipenem. It has most powerful bactericidal effect on most bacteria, and has super broad antibacterial spectrum. It has most powerful bactericidal effect on most bacteria, and has super broad antibacterial spectrum. Nearly all gram-negative and gram-positive bacteria infection can be treated with this kind of drug. Nearly all gram-negative and gram-positive bacteria infection can be treated with this kind of drug.

45. Other β-lactams Monobactams Aztreonam and carumonam belong to Monobactams. Aztreonam and carumonam belong to Monobactams. It is highly resistant to ß -lactamases. It is highly resistant to ß -lactamases. It is effective in treating Gram-negative urinary tract infections, lower respiratory tract, skin, intra abdominal, gynecologic infections and septicemia. It is effective in treating Gram-negative urinary tract infections, lower respiratory tract, skin, intra abdominal, gynecologic infections and septicemia. Aztreonam may be given together with other antibiotics which are active against Gram-positive bacteria and anaerobes in mixed infections. Aztreonam may be given together with other antibiotics which are active against Gram-positive bacteria and anaerobes in mixed infections.

46. Other β-lactams Oxacephems Latamoxef and flomoxef belong to Oxacephems. Latamoxef and flomoxef belong to Oxacephems. It has similar spectrum, antibacterial activity with ceftazidime. It has similar spectrum, antibacterial activity with ceftazidime. It has better activity on anaerobe than first, second and third generation cephalosporins. It has better activity on anaerobe than first, second and third generation cephalosporins.

47. Other β-lactams β-lactamase inhibitor This kind of drug include clavulanic acid, sulbuctam and tazobactam. This kind of drug include clavulanic acid, sulbuctam and tazobactam. These agents are potent inhibitors of many kind of ß -lactamases and are used together with penicillins to protect them from inactivation. These agents are potent inhibitors of many kind of ß -lactamases and are used together with penicillins to protect them from inactivation.

48. Home work 1. How are agents in this chapter classified? 1. How are agents in this chapter classified? 2. What are the major differences among the cephalosporin antibiotics by generations? 2. What are the major differences among the cephalosporin antibiotics by generations? 3. Describe the pharmacological effects of penicillin G. 3. Describe the pharmacological effects of penicillin G.