Chapter 40 Aminoglycosides and Polymyxins

Department of pharmacology

Liu xiaokang(刘小康）2010,3

Aminoglycosides

• Members: • Streptomycin, kanamycin , tobramycin,

neomycin, gentamicin, sisomicin, netilmicin, Amikacin.

• Structure:

Common properties of aminoglycosides

• Antibacterial activity: • Bactericidal antibiotics with special prop

erties as follows: (1) Concentration dependent bactericidal effect; (2) only acting aerobes; (3) significant PAE; (4) First exposure effect (FEE); (5) increased activity in alkalescent environment.

• Antibacterial spectrum: • Gram-negative aerobic rods, E. coli, Pseu

d. aeruginosa, Protues, Klebsiella, Eterobacter, Shigella, Citrobacter. Aminoglycosides and β-lactams are synergistic and nearly always used in combination with a ß-lactam to extend coverage to possibly gram-positive microbes.

• Mechanisms: • (1) interference with "initiation complex" of

peptide formation; (2) causing misreading of mRNA which results in incorrect amino acid incorporation; (3) blocking the release of synthesized polypeptide; (4) promotion of polysomal dissociation into nonfunctional monosome. These combined effects, occurring at the same time, are probably responsible for aminoglycoside bactericidal properties.

• Pharmacokinetics: • Cannot absorb by oral administration.

Distributed in most tissues, especially high concentration in kidney, cochlea, vestibular apparatus. No metabolism and Excreted by glomerular filtration.

• Clinical uses:

• (1) used in most gram-negative aerobic bacillary infection, septicaemia, pelvic and abdominal sepsis. (2) Bacterial endocarditis, (3) other infections: tuberculosis.

• Adverse reactions: • (1) Ototoxicity: both vestibular and audit

ory damage may occur; • (2) Nephrotoxicity: dose-related, usually

reversible; • (3) Neuromuscular blockade, may impair

neuromuscular transmission and aggravate myasthenia gravis, or cause a transient myasthenic syndrome in patients whose neuromuscular transmission is normal;

• (4) Allergic reactions: rashes, fever and angioedema.

• Resistance: • (1) plasmid-mediated aminoglycoside inact

ivating enzymes.• (2) Membrane permeability changed, caus

ed failure of aminoglycosides to penetrate the cytoplasmic (inner) membrane, the porin protein changed or the oxygen dependent active transport reduced;

• (3) target modification, 30s subunit modified, hence reduced the affinity of streptomycin with rRNA.

Properties and uses of commonly used

aminoglycosides

• Streptomycin: • (1) main use: second-line treatment for tubercu

losis, used only in combination with other antimicrobials (otherwise rapid emergence of resistance);

• (2) In combination with oral tetracycline, i.m. streptomycin may be used in treating: plague and tularemia;

• (3) In combination with penicillin: treatment for enterococcal endocarditis and viridans streptococcal endocarditis (two-week regimen).

• Adverse Reactions: • Fever, rash (hypersensitivity), Most

serious toxic effect: vestibular toxicity which tends to be irreversible. Streptomycin administration during pregnancy may result in deafness in the newborn.

• Kanamycin & Neomycin: • (1) Kanamycin and Neomycin: Active ag

ainst gram-positive, gram-negative and some mycobacteria.  Pseudomonas and streptococci are resistant to kanamycin and neomycin. (2) Mechanisms of action and resistance follow that of other aminoglycosides; (3) Cross-resistance between these agents and kanamycin and neomycin;

• (4) clinical uses:  Kanamycin: Only used to drug resistant tuberculosis. Neomycin: topical and oral use only due to toxicity associated with parenteral administration; Given prior to elective bowel surgery, reducing aerobic bowel flora.

• (5) Adverse efeccts: Ototoxicity (auditory) and nephrotoxicity.

• Gentamicin:  • Antibacterial activity: Gentamicin is effe

ctive against gram-positive and gram-negative microbes, mainly used for G － bacteria infection. Active alone but shows synergism with β-lactam antimicrobials in managing Pseudomonas, Proteus, Enterobacter, Klebsiella, Serratia, Stenotrophomonas and other gram-negative rods. No activity against anaerobes.

• Clinical uses: • (1) Primary clinical use: Treatment of severe gr

am-negative bacterial infections (sepsis/pneumonia) when the bacteria is likely resistant to other antibiotics.

• (2) The combination of gentamicin and a cephalosporin or penicillin may be life-saving in the immunocompromised patient.

• (3) Gentamicin + penicillin G: viridans streptococcal endocarditis

• (4) Gentamicin + nafcillin in some cases of staphylococcal endocarditis.

• (5) Gentamicin should not be used as a single agent due to rapid development of resistance.

• (6) Aminoglycosides should not be used as single therapy in pneumonia due to poor tissue penetration.

• (7) Nephrotoxicity: requires serum gentamicin monitoring if administration exceeds a few days.

• Adverse Reactions: • (1) Nephrotoxicity;

• (2) Deafness;

• (3) Vestibular toxicity which tends to be irreversible.

• Tobramycin: • Similar antimicrobial spectrum to

gentamicin. Some cross-resistance possible.

• Clinical use: Stronger acting than gentamicin to Pseudomonas, Proteus, Enterobacter and Klebsiella.

• Adverse Reactions: Nephrotoxicity, Deafness and Vestibular toxicity that tends to be irreversible, but lighter than gentamicin.

• Sisomicin: • similar with gentamicin.

• Amikacin: • Semisynthetic derivative of kanamycin,

but less toxic. Amikacin has the broadest antibacterial spectrum in aminoglycosides, and may be used against microbes resistant to gentamicin or tobramycin, because it is resistant to enzymes that inactivate those agents.

• Amikacin is often effective in treating multi-drug resistant strains of Mycobacterium tuberculosis. Kanamycin resistant isolates are likely to exhibit cross-resistance to amikacin.  Amikacin is ototoxic (auditory component especially) and nephrotoxic, as are all aminoglycosides.

• Netilmicin: • Antibacterial spectrum: Enterobacter an

d some G+ cocci. Clinical use is similar with amikacin. Ototoxicity and nephrotoxicity are lower than other aminoglycosides.

Polymyxins

• polymyxin B • Antibacterial activity: narrow spectru

m, acting on some gram-negative rods.

• Mechanism: • impair plasmamembrane, leading the lea

kage of life dependent material, hence destroy the cell.

• Clinical uses: (1) drug resistance Pseud aeruginosa infection; (2) drug resistance G– rods infection; (3) topical use.

• Adverse reaction: Nephrotoxicity; neurotoxicity; allergic reaction.

• Resistance: Very few resistant strains have been found.

• (The end)