Understanding β-Lactam Antibiotics: Penicillins and Beyond

1. β－Lactam Antibiotics Penicillins 【 Antibacterial activity 】 Gram-positive coccus Gram-negative coccus Gram-positive bacilli Helicoids

2. Semisynthetic penicillin Penicillinase-resistant penicillin( Oxacillin ) (1) They kill penicillinase-producing staphylococci (2) They can’t kill Methicillin-resistant strains of Staphylococcus aureus (MRSA)

3. Extended spectrum penicillins (Ampicillin) • They are more effective against gram-negative bacilli • They can not kill pseudomonas aeruginosa Antipseudomonal penicillins Carbenicillin Piperacillin

4. Cephalosporins Feature ＋＋＋

5. Other β-lactams antibiotics Carbapenems Imipenem+ cilastatin β-lactamase inhibitors Clavulanic acid + Amoxicillin

6. Chapter 37 Macrolides Lincomycins Polypeptide antibiotics

7. Macrolides Erythromycin Clarithromycin Azithromycin

8. 一、Erythromycin 【Pharmacokinetics】 • Erythromycin base is destroyed by gastric acid • It distributes well to all body fluids including prostatic fluid ,but it does not enter the cerebrospinal fluid (CSF) • Erythromycin is extensively metabolized and is excreted in the bile, and only 5% is excreted in the urine.

9. 【Antibacterial activity 】 • Erythromycin is bacteriostatic • It is effective against gram-positive organisms • It is active against some gram-negative organisms • Mycoplasma, Chlamydozoan, Legionella and campylobacteria are susceptible.

10. P A P A P A 【Mechanism of action】 Inhibit protein synthesis Erythromycin(50S) translocase

11. 【Clinical uses】 • Gram-positive coccus infection • staphylococci: bouton (boil) • streptococci: pharyngitis, febris rubra • streptococcus pneumoniae: pneumonia genuina • 2. Corynebacterium diphtheriae • 3. Chlamydial infections • urethral, endocervical, rectal, epididymal, urogenital • 4. Mycoplasmal pneumonia • 5. Legionella pneumonia

12. 【Adverse effect】 1. Gastrointestinal effects Anorexia, nausea, vomiting, and diarrhea 2. Cholestatic jaundice estolate form of erythromycin 3. Ototoxicity Transient deafness Contraindications: hepatic dysfunction

13. 【Drug resistance】 1. Reduced permeability of the cell membrane or active efflux 2. Modification of the ribosomal binding site 3. Production of esterases that hydrolyze macrolides methylation of an adenine of the 23S bacterial ribosomal RNA

14. 二、Clarithromycin • Its activity against Chlamydia, Legionella and Ureaplasma is higher than that of erythromycin. • It has lower frequency of gastrointestinal intolerance

15. 三、 Azithromycin • Azithromycin is more active against Haemophilus influenzae and Chlamydia than erythromycin • It is less active against streptococci and staphylococci • It is now used for urethritis caused by Chlamydia trachomatis. • It is rapidly absorbed and well tolerated orally.

16. Section 2 Lincomycins   Lincomycin Clindamycin

17. 【 Antibacterial action and Clinical uses 】 1. Clindamycin is significantly effective against anaerobic bacteria 2. It is employed primarily in the treatment of infections caused by anaerobic bacteria 3. Enterococci and clostridium difficile are resistant 4. It distributes well into bone, so treats medullitis 5. It does not penetrate into cerebrospinal fluid , not use to treat Epidemic meningitis alone

18. 【Adverse effect 】 vancomycinmetronidazole Fatal pseudomembranous colitis Impaired liver function

19. Section 3 Polypeptide antibiotics Vancomycins polymyxins

20. 一、Vancomycin 【Antibacterial activity 】 • It is bactericidal agent • It is primarily active against gram-positive bacteria • (MRSA and MRSE),but enterococci are resistant • 3. All species of gram-negative bacilli and mycobacteria are resistant to vancomycin

21. Vancomycin 【Mechanism of action】

22. 【Clinical use and Adverse effect 】 1. Gram-positive bacteria infections: pneumonia, empyema, endocarditis, osteomyelitis, and soft-tissue abscesses, MRSA infection 2. Fatal pseudomembranous colitis due to Clostridium difficile or staphylococci 3. Adverse effects: ototoxicity, nephrotoxicity , "red man syndrome

23. 二、Polymyxins • They are bactericidal agent, active against gram-negative bacilli • 2. They increased permeability of the bacterial membrane resulting bacterial cell death • 3. They are available for external otitis, corneal ulcers caused by Pseudomonas • 4. Adverse effects: nephrotoxicity, neurotoxicity, hypersensitive reaction

24. Chapter 38 Aminoglycosides Streptomycin Neomycin Kanamycin Amikacin Gentamicin Tobramycin

25. 【Antibacterial activity】 Antibacterial spectrum : • All aminoglycosides are bactericidal • They are effective against aerobic gram-negative bacilli • They are ineffective against anaerobic organisms

26. P A P A Decoding 【Mechanism of action】 P A interfere with the initiation complex nonfunctional or toxic protein synthesis aminoglycosides(30S,A) breakup of polysomes into nonfunctional monosomes P A

27. 【Pharmacokinetics 】 • Aminoglycosides must be given parenterally • High concentrations accumulate in the renal cortex and in the endolymph and perilymph of the inner ear • All may accumulate in fetal plasma and amniotic fluid. • All are rapidly excreted into the urine

28. 【Clinical uses】 • Aminoglycosides are mostly used to treat infection caused by gram-negative bacteria • Penicillin combination with aminoglycoside is used for treatment of enterococcal endocarditis , streptococcal and staphylococcal endocarditis

29. 【Adverse effect】 dizziness, visual extinction, ocular tremor, nausea, vomiting, ataxia. • Ototoxicity ： • vestibular dysfunction • Injury of cochlear auditory nerve • Nephrotoxicity: • 3. Neuromuscular paralysis: • 4. Allergic reactions: ear noises hearing diminution permanent deafness

30. 【Drug resistance】 • Synthesis of enzymes that modify and inactivate aminoglycoside antibiotics. • Altered target site • Decreased uptake of drug

31. Chapter 39 Tetracyclines and Chloramphenicol Section 1 Tetracyclines Tetracycline Doxycycline Demeclocycline Minocycline

32. 【Antibacterial activity】 • Tetracyclines are broad spectrum bacteriostatic • antibiotics • 2. They are active against many gram-positive and gram-negative bacteria • 3. They are also active against Rickett's organism, helicoid, mycoplasma and Chlamydia

33. P A P A Tetracyclines (30S,A) 【Mechanism of action】 • tetracyclines enter microorganism by passive diffusion and an energy-dependent process of active transport. • tetracyclines bind reversibly to the 30S subunit of the bacterial ribosome

34. 【Pharmacokinetics】 • Tetracyclines are adequately but incompletely • absorbed after oral ingestion • 2. Tetracyclines cross the placental barrier and concentrate in fetal bones and dentition • 3. Tetracyclines are metabolized in liver and then are excreted from kidney, except doxycycline

35. 【Clinical uses】 • Rickettsial infection: fever, chill, ache in bones and joints • Chlamydiae infection: pneumonia , urethritis, trachelitis, ophthalmia and trachoma • Mycoplasma infection: mycoplasmal pneumonia • Spirochetal infection: lyme disease • Bacterial infection: cholera

36. 【Adverse effect 】 • Gastric discomfort: Nausea, vomiting, and diarrhea • Bony structures and Teeth :discoloration and hypoplasia of the teeth and a temporary stunting of growth • Fatal hepatotoxicity: in pregnant women • Phototoxicity: severe sunburn

37. 4. Vestibular problems: dizziness, nausea, vomiting 5. Pseudotumor cerebri: Benign intracranial hypertension , headache , blurred vision 6. Superinfections: pseudomembranous enterocolitis caused by Clostridium difficile. 7. Contraindications: renally-impaired patients , pregnant or breast-feeding women, or in children \under 8 years of age.

38. 【Drug resistance】 • Decreased intracellular accumulation • production of protected proteins that interfere with tetracycline binding to the ribosome • Enzymatic inactivation of tetracyclines

39. Section 2 Chloramphenicol 【 Antibacterial action】 • Chloramphenicol is either bacteriostatic or bactericidal • It is active against both aerobic and anaerobic gram-positive and gram-negative organisms • It has effective against rickettsiae, helicoids, Chlamydia and mycoplasma.

40. P A P A 【Mechanism of action】 Chloramphenicol(50S,A) Peptidyl transferase

41. 【pharmacokinetics】 • Chloramphenicol may be administered either intravenously or orally • It penetrate blood-brain barrier, placental barrier, blood-ocular barrier • It is inactivated by conjugation with glucuronic acid in liver, secreted by the renal tubule

42. 【Clinical uses】 • Bacterial meningitis: meningococcal meningitis • Rickettsial infections: typhus or Rocky Mountain spotted fever • Eye infection: outer eye infection, intraocular infection, eyeball infection • Anaerobic infection: peritoneal abscess, pelvic inflammation and peritonitis

43. 【Adverse effect】 • Bone marrow depression • Aplastic anemia • Gray baby syndrome: • poor feeding, depressed breathing, • cardiovascular collapse, cyanosis

44. 【Drug resistance 】 • Produce inactivator： acetyl coenzyme A transferase • Membrane permeability is decreased, chloramphenicol penetrate the organism less