1. Chapter 37 Aminoglycosides( 氨基糖苷类 ) & Polymyxins( 多黏菌素类 ) Huifang Tang tanghuifang@zju.edu.cn

2. Aminoglycosides （氨基苷类） Summarization of aminoglycosides The aminoglycosides are compounds contanining characteristic amino sugars joined to a hexose nucleus in glycosidic( 糖苷） linkage. Most amino- glycosides, which are prepared by natural fermentation from various species of streptomyces, are a group of bactericidal drugs sharing chemical, antimicrobial, pharmacological, and toxic characteristics.

3. Structure of streptomycin

4. Structures of several important aminoglycoside antibiotics.

6. Natural Aminoglycosides 链霉素 (streptomycin) 庆大霉素 (gentamicin) 链霉素 (streptomycin) 庆大霉素 (gentamicin) 新霉素 (neomycin) 西索米星 (sisomicin) 新霉素 (neomycin) 西索米星 (sisomicin) 妥布霉素 (tobramycin) 小诺米星 (micronomicin) 妥布霉素 (tobramycin) 小诺米星 (micronomicin) 卡那霉素 (kanamycin) 卡那霉素 (kanamycin) 大观霉素 (spectinomycin) 大观霉素 (spectinomycin) SemisyntheticSemisynthetic Aminoglycosides 阿米卡星 (amikacin) 奈替米星 (netilmicin) Natural Aminoglycosides 链霉素 (streptomycin) 庆大霉素 (gentamicin) 链霉素 (streptomycin) 庆大霉素 (gentamicin) 新霉素 (neomycin) 西索米星 (sisomicin) 新霉素 (neomycin) 西索米星 (sisomicin) 妥布霉素 (tobramycin) 小诺米星 (micronomicin) 妥布霉素 (tobramycin) 小诺米星 (micronomicin) 卡那霉素 (kanamycin) 卡那霉素 (kanamycin) 大观霉素 (spectinomycin) 大观霉素 (spectinomycin) SemisyntheticSemisynthetic Aminoglycosides 阿米卡星 (amikacin) 奈替米星 (netilmicin) Aminoglycosides （氨基苷类）

8. Aminoglycosides Spectrum of activity Aminoglycosides are effective against aerobic gram-negative bacteria, especially in bacteremia, sepsis, or endocarditis.

9. Mechanism of action The mechanism of Aminoglycosides is to inhibit protein synthesis in susceptible microorganisms. by interfering with the initiation complex of peptide formation. inducing misreading of the code on the mRNA template, which causes incorporation of inappropriate amino acid into peptide. by rupturing the polysomes into monosome, which become nonfunctional. Aminoglycosides

11. 氨基苷类 四环素类 大环内酯类 氯霉素类 林可霉素类 Inhibiting protein synthesis

12. Mechanisms of resistance Three principal mechanisms have been established: (1) production of a transferase enzyme or enzymes inactivates the aminoglycoside by adenylylation, acetylation, or phosphorylation. This is the principal type of resistance encountered clinically. (Specific transferase enzymes are discussed below.) (2) There is impaired entry of aminoglycoside into the cell. This may be genotypic, ie, resulting from mutation or deletion of a porin protein or proteins involved in transport and maintenance of the electrochemical gradient; or phenotypic, eg, resulting from growth conditions under which the oxygen-dependent transport process described above is not functional. (3) The receptor protein on the 30S ribosomal subunit may be deleted or altered as a result of a mutation.

13. Pharmacokinetics poorly absorbed from the gastrointestinal tract. must be given intramuscularly or intravemously for systemic infection. excreted almost entirely unchanged by glomerular filtration, which is greatly reduced in renal impairment, causing toxic blood levels. Aminoglycosides

14. Adverse effects Ototoxicity Aminoglycosides are potentially toxic to branches of the eighth cromial nerve. The evidence indicates that the sensory receptor portions of the inner ear ( hair cells of the cochlea) are affected rather than the nerve itself. cochlear damage( 耳蜗损伤 ): sisomicin>gentamicin>tobramycin Kanamycin>Amikacin> sisomicin>gentamicin>tobramycin vestibular impairment( 前庭受损 ): Kanamycin>Streptomycin>sisomicin> gentamicin> tobramycin Aminoglycosides

15. Nephrotoxicity Nephrotoxicity may develop during or after use of an aminoglycosides, those elderly, debilitated patients, and patients with preexisting renal dysfunction. Nephrotoxicity is dose dependent and damage to the proximal tubular epithelium usually begins after five to seven days of therapy. The toxicity results from accumulation and retention of aminoglycosides in the proximal tubular cells. The renal injury may lead to acute renal failure. Neomycin>Kanamycin>gentamicin>Streptomycin or tobramycin>Amikacin Aminoglycosides

16. Neuromuscular blockade The aminoglycosides rarely cause neuromuscular blockade that can lead to progressive flaccid paralysis and potentially total respiratory arrest. The risk is greatest after rapid iv administration. Neomycin>Streptomycin >Amikacin or Kanamycin>gentamicin > tobramycin Aminoglycosides

17. Clinical uses Aminoglycosides are mostly used against gram- negative enteric bacteria, especially when the isolate may be drug-resistant and when there is suspicion of sepsis. They are almost always used in combination with a - lactam antibiotic to extend coverage to include potential gram-positive pathogens and to take advantage of the synergism between these two classes of drugs. –Penicillin-aminoglycoside combinations also are used to achieve bactericidal activity in treatment of enterococcal endocarditis and to shorten duration of therapy for viridans streptococcal and staphylococcal endocarditis. Which aminoglycoside and what dose should be used depend on the infection being treated and the susceptibility of the isolate.

18. Streptomycin （链霉素） Spectrum of activity and therapy of Streptomycin (1) most gram-negative bacilli and some gram-positive cocci. (2) organisms that cause plague( 鼠疫） and in combination with penicillin G against bacterial endocarditis. (3) antituberculosis agent. A major disadvantage of streptomycin therapy is the development of frequent bacterial resistance to the drug. Aminoglycosides

19. Untoward effects of streptomycin Hypersensitivity reactions can occur. Labyrinthine damage ( 迷路破坏 ) and vestibular disturbances can occur. Streptomycin should not be given with other ototoxic drugs. Renal effects are minimal at normal doses. Neuromuscular junction blockade may occur when streptomycin is given at high doses and in combination with curariform drugs ( 箭毒样药物 ). Aminoglycosides

20. Gentamicin It is effective against both gram-positive and gram-negative organisms, and many of its properties resemble those of other aminoglycosides. It is active alone, but also as a synergistic companion with –lactam antibiotics, against pseudomonas, proteus, enterobacter, klebsiella, serratia, stenotrophomonas, and other gram-negative rods that may be resistant to multiple other antibiotics. Like all aminoglycosides, it has no activity against anaerobes. Gentamicin

21. Clinical uses Intramuscular or intravenous administration used in the treatment of a serious infections caused by a large number of gram-negative organisms. It usually is used in combination with a second agent, because an aminoglycoside alone may not be effective for infections outside the urinary tract. Gentamicin is of the first choice when these infections occurs 1) urinary tract infections, bacteremia resulting from Escherichia coli. 2) bile duct and urinary tract infections caused by proteus mirabilis. Gentamicin

22. Gentamicin combined with carbenicillin is of the first choice for the treatment of infected burns, bacteremia, urinary tract infection resulting from pseudomonas aeruginosa. Gentamicin

23. Topical administration Creams, ointments, and solutions containing 0.1–0.3% gentamicin sulfate have been used for the treatment of infected burns, wounds, or skin lesions and the prevention of intravenous catheter infections. Topical gentamicin is partly inactivated by purulent exudates. Ten mg can be injected subconjunctivally for treatment of ocular infections. Gentamicin

24. Intrathecal administration Meningitis caused by gram-negative bacteria has been treated by the intrathecal injection of gentamicin sulfate, 1–10 mg/d. However, neither intrathecal nor intraventricular gentamicin was beneficial in neonates with meningitis, and intraventricular gentamicin was toxic, raising questions about the usefulness of this form of therapy. Moreover, the availability of third- generation cephalosporins for gram-negative meningitis has rendered this therapy obsolete in most cases. Gentamicin

25. Untoward effects of gentamicin  Ototoxicity ( 耳毒性 ) is the most serious effect.(The incidence of ototoxicity is in part genetically determined, having been linked to point mutations in mitochondrial DNA, and occurs in 1–5% for patients receiving gentamicin for more than 5 days. )  Nephrotoxicity can occur.  Hypersensitivity can also occur. Gentamicin

26. Tobramycin 妥布霉素 Tobramycin has an antibacterial spectrum similar to that of gentamicin. The pharmacokinetic properties of tobramycin are virtually identical with those of gentamicin. Tobramycin

27. Tobramycin vs Gentamicin Spectrum of activity of Tobramycin Tobramycin has almost the same antibacterial spectrum as gentamicin with a few exceptions. Gentamicin is slightly more active against serratia, whereas tobramycin is slightly more active against pseudomonas （假单胞 菌属） ; Enterococcus faecalis is susceptible to both gentamicin and tobramycin, but E faecium is resistant to tobramycin. Adverse effects of Tobramycin Ototoxicity Nephrotoxic –Nephrotoxicity of tobramycin may be slightly less than that of gentamicin, but the difference is clinically inconsequential. Tobramycin

28. Clinical uses Gentamicin and tobramycin are otherwise interchangeable clinically. Tobramycin is also formulated in solution (300 mg in 5 mL) for inhalation for treatment of Pseudomonas aeruginosa lower respiratory tract infections complicating cystic fibrosis. Tobramycin

29. Neomycin & Kanamycin Antimicrobial Activity & Resistance –gram-positive and gram-negative bacteria and some mycobacteria. –Pseudomonas and streptococci are generally resistant. –The widespread use of these drugs in bowel –preparation for elective surgery has resulted in the selection of resistant organisms and some outbreaks of enterocolitis in hospitals. –Cross-resistance between kanamycin and neomycin is complete. Neomycin & Kanamycin

30. Clinical Uses Neomycin and kanamycin are now limited to topical and oral use. Neomycin is too toxic for parenteral use. With the advent of more potent and less toxic aminoglycosides, parenteral administration of kanamycin has also been largely abandoned. Paromomycin has recently been shown to be effective against visceral leishmaniasis when given parenterally, and this serious infection may represent an important new use for this drug. Neomycin & Kanamycin

31. Kanamycin  Kanamycin has a more limited spectrum of activity than Gentamicin has.  It is ineffective against Pseudomonas and most gram-positive organisms.  Its clinical uses almost replaced by gentamicin. Neomycin & Kanamycin

32. Neomycin 新霉素 Spectrum of activity of Neomycin Neomycin has a spectrum of activity similar to that of kanamycin. Untoward effects of Neomycin Renal damage, eighth-nerve damage resulting in nerve deafness. Neomycin & Kanamycin

33. Adverse Reactions  All members of the neomycin group have significant nephrotoxicity and ototoxicity.  Auditory function is affected more than vestibular function. Deafness has occurred, especially in adults with impaired renal function and prolonged elevation of drug levels.  The sudden absorption of postoperatively instilled kanamycin from the peritoneal cavity (3–5 g) has resulted in curare-like neuromuscular blockade and respiratory arrest. Calcium gluconate and neostigmine can act as antidotes.  Although hypersensitivity is not common, prolonged application of neomycin- containing ointments to skin and eyes has resulted in severe allergic reactions. Neomycin & Kanamycin

34. Amikacin 阿米卡星, 丁胺卡那霉素 Specturm of activity of Amikacin Amikacin has a spectrum of activity similar to that of Gentamicin but often is reserved for serratia ( 沙雷菌属） infections or for cases where resistance to Gentamicin has emerged. Adverse effects of Amikacin Ototoxicity is the most serious side effect. Amikacin

35. Spectinomycin Spectinomycin is an aminocyclitol antibiotic that is structurally related to aminoglycosides. It lacks amino sugars and glycosidic bonds.

37. Tobramycin: Intravenous; more active than gentamicin versus pseudomonas; may also have less nephrotoxicity Amikacin: Intravenous; resistant to many enzymes that inactivate gentamicin and tobramycin; higher doses and target peaks and troughs than gentamicin and tobramycin Streptomycin: Intramuscular, widespread resistance limits use to specific indications such as tuberculosis and enterococcal endocarditis Neomycin: Oral or topical, poor bioavailability; used before bowel surgery to decrease aerobic flora; also used to treat hepatic encephalopathy Spectinomycin: Intramuscular; sole use is for treatment of antibiotic-resistant gonococcal infections or gonococcal infections in penicillin-allergic patients

38. Polymyxins 多粘菌素类 There are five polymyxins. A, B, C, D, E, Polymyxin E, 多粘菌素 E (Colistin, 抗敌素 ) is frequently used in clinics. Polymyxins

39. Spectrum of activity Polymyxins are active mainly against gram- negative bacilli, particulary pseudomonas and coliform organisms. Mechanism of action of polymyxins Polymyxins act by attaching to the cell membranes of bacteria and other membranes rich in phosphatidylethanolamin ( 磷脂酰乙醇胺 ) and disrupting the osmotic properties and transport mechanisms of the membrane. This results in leakage of macromolecules and death of the cell. Polymyxins

40. Therapeutic uses of Polymyxins Infections caused by pseudomonas or coliform bacteria resistant to other antimicrobial drugs. Polymyxins

41. Untoward effects Neurotoxic effects Polymyxin can cause paresthesias, dizziness and incoordination. Nephrotoxic effects Some proteinuria, hematuria are the evidence of tubular injury. Polymyxins